 Thank you, and I am not a professional researcher. I'm a hobbyist researcher, so I want to extend particularly great appreciation to this community to you and to the ancestral health health Symposium to listen to me today Unfortunately, I deeply fell in love with this topic And so I'm going to have to speak really fast and maybe even run into the question time a little bit But I hope it'll still be comprehensible. I think this is the thing Or maybe just this Okay, so if you've heard about Uric acid at all it's probably in the context of gout because gout is associated with high uric acid the thing is Not to everyone who has high uric acid gets gout in fact only a small proportion of them do and it's even the case that out of Everyone who has gout only there's a significant minority that don't even have high uric acid Nonetheless, we don't really know very much detail about why it sometimes crystallizes and why it's white and other people it doesn't However, I'm told it's absolutely excruciating I've seen it negatively compared to childbirth and it is associated with high uric acid levels And so I don't blame you for trying to avoid them But another reason that uric acid gets a bad rap is because it's been associated with metabolic syndrome in this Review, for example, we have many studies that are making such an association and a handful of them actually have a relative risk of Over two so it may potentially be serious. I Think high uric acid is a very good candidate for a mismatch argument because as I will show you High uric acid seems to be highly selected for in humans and yet it's associated with these problems So it's possible even that if if we were somehow in a situation where gout and metabolic syndrome were not a real risk That there could actually still be an advantage to higher levels So in order to get clearer on this I'm going to talk about some biochemistry some physiology some evolutionary biology and some cross species analysis Like with anything in the blood Your level is always going to be a consequence of how much is being produced and how much is being used or excreted So from the production side, uric acid is always made out of purines Purines are just a class of molecules that happen to be particularly important to life because a couple of our nucleotides are actually based on it in addition to that a Denocene is made out of adenine and so anything that involves ATP or pure energetic sigling in the brain is also Involved with purines So that means that everything that's living has purines in it And if you're gonna eat something that's if you're gonna eat animal foods or particularly organ foods or seafood You're going to get a lot of incoming purines that are then metabolically broken down And that is one contributor to levels of uric acid in the blood But then of course, we're also made of meat So we're constantly producing our own purines and sometimes they get recycled and sometimes they don't so endogenous synthesis and Metabolizing of purines is actually where most of our blood uric acid comes from Then if you get some kind of tissue damage that can also Be incorporated into blood because anytime that a tissue breaks down that floods the system So people who have chemo or some kind of big injury will sometimes get dangerously high levels of uric acid You might think that then if all people Vegans would have the lowest levels of uric acid But at least in this study that didn't turn out to be the case vegans in this study had the highest levels of uric acid even Higher than the meat eaters They didn't come up with this idea, but I speculate that the reason for this is that a Chronic deficiency in essential proteins is going to require that you break down some of your own muscle tissue to make up for that deficit Okay, so what about the excretion side? Here's a cartoon of uric acid passing through the kidneys and there are pathways for secreting it and for Reabsorbing it there are different polymorphisms involved in the transport and the majority of people who have problems with hyperurethemia Have polymorphisms in the excretion side, but even not taking those into account 90% or more of the uric acid that comes into your kidneys gets Reabsorbed and at risk of sounding like I'm anthropomorphizing that seems quite intentional So just to summarize the different ways that Ceramuric acid is a combination of is you've got dietary peering intake. You've got your own endogenous synthesis I've circled fructose and I'm gonna come back to that Then you have how much you're salvaging versus not and then on the other side you have how much you're excreting versus absorbing Okay, so the other thing that seems really intentional from a species point of view is that most animals and other animals other mammals have uricase which Regulates their level of uric acid by breaking it down into a much more soluble compound to land twin before Excreting it and so that reduces the risks that are associated with having high uric acid We lost this ability a long time ago with a series of mutations starting over 20 million years ago in the primate line So this lack of uricase we share with other great apes here is a diagram of splits related to uricase and the the Changes are all changes in the protein of the uricase function and the pink numbers are just showing how much uric acid can Be broken down, so the one that I've circled you can see that's the first major change in how much uric acid We're able to break down and that's at the primate level But then from there on it just gets lower and lower and lower and when you get up to that right-hand side You start seeing these genes that are actually stopping the function completely and one thing that's really interesting to notice about that Is that it happens independently in different lines and there are redundancies of it It's not just one thing that you could maybe say is accidental And at the same time as all that was happening on the excretion side We also have the you're a one transporter which is in charge of How much absorption can happen and I've circled the words high affinity and low capacity high affinity means that it takes Only a very small amount of uric acid to be present to get that reabsorption happening and low capacity means it gets Saturated really quickly so once you get to a certain level it doesn't absorb anymore and the total of those ideas is that you've got a really tightly regulated system and Then I just wanted to draw attention to the fact that there are differences even between the human and chimpanzee level which may be really important because Among all the primates we have the highest uric acid level So if you look at primates all of the ones under that uricase mutation line don't have functional uricase, but there are still differences in our base levels So there has to be more to it than just that So all of these factors combined Make it highly probable that high uric acid in humans is not an accident first of all It's species-wide right so if you if you think about a loss of function gene And it's just because we don't really need it you would expect to see different polymorphism Surviving because there's no particular advantage to having it or not having it. That's not what happened here There are independent lines of it. It's happened in multiple cases with redundancy and Then of course that reabsorption which in the words of Tavchiga and Striegel Would be very strange for an indifferent substance and Finally the level that we've ended up with is really close to the solubility limit It's about as high as you can go before it. It's just going to go into crystals no matter what you do Since uric acid is a breakdown product It's tempting to think of it as just a waste product like other waste products The reason to exist is just so that it can be excreted and I bring this up because I'm reminded of older literature About ketone bodies where they talk about it as a byproduct of fat metabolism and how it can be toxic when it's accumulated But uric acid is actually used for something so it's an antioxidant There are a few different pathways that in certain cases can actually be really important Some people argue that it's the most important antioxidant that we have of course. They're all important So it's a funny argument But it's been shown to be more powerful than vitamin C that it it's in some ways of measuring it more than half of our Antioxidant activity it can chelate iron. It's really important for extra that exercise induced oxidation It prevents lipid peroxidation And that leads us to the earliest hypothesis about uricase, which is the antioxidant longevity Apothesis so it was first mentioned by proctor and then popularized and expanded upon by Bruce Ames and the idea is that When you look at across species the ones who have the highest level of uric acid also have the highest longevity And of course we we have an idea that oxidative stress and longevity are somehow related But it turns out experimentally that if you just boost antioxidants it doesn't necessarily translate into longer life spans and People have pointed out that Within the human species high uric acid is not necessarily correlated to longer life span Especially when you take into account that metabolic syndrome effect Another component of the antioxidant theory is to notice that in the words of Rick Johnson We are double knockouts. So Another 20 or 30 million years before the uricase stuff started happening. We lost our ability to synthesize vitamin C Why did that happen? Well, some people have suggested again that we just didn't need it and of course that would be more compelling if various Polymorphisms existed, which they don't There are multiple stop genes for this as well Another suggested advantage is that when you create an antioxidant Indogenously it actually creates oxidation and so the net oxidation advantage is Maybe a wash and therefore the idea is that if you're going to get all of your vitamin C Exogenously that's a win over endodgiously because you don't get that oxidation step first But I don't find that very compelling either because you could keep the ability to synthesize it when you need it And only bring it into play when you don't get it The more compelling idea that I've heard about it is that it actually spares glucose and sparing glucose Especially for a large-brained animal could be really important Ascorbic acid vitamin C is made out of glucose. So that's one potential reason Regardless of why we have the vitamin C knockout once we have that we can build on that and say well now the motivation for or the advantage to having high uric acid is that it actually Improves the ability to use vitamin C. It itself is an antioxidant And so between the two we get more antioxidant capacity given that we started from this low vitamin C state And if you look at the proportions in humans Uric acid to vitamin C we have about four times as much uric acid as vitamin C Whereas those who are synthesizing it have only about a third the level of uric acid and some three to four times higher the Ascorbic acid so this idea that one's taking over the function of the other is kind of compelling and So the whole idea behind Bruce Ames's theory is that basically uric acid is a compensation for that previous mutation another important hypothesis is the intelligence hypothesis it it was noticed that prominent intelligent people tended to have high uric acid and The association was kind of weak people started looking into it a lot and after some more study They they decided that it was actually mode higher motivation and not intelligence per se So people who are really prominent in their field who had a lot of influence tended to have high uric acid But high intelligence wasn't enough. You had to also have this Motivation to use it and there's sort of a comparison to cortisol and then of course it was noticed another supporting factor for this hypothesis is that caffeine and theobromine are Are purines and have stimulant effects on the brain? And so the idea is maybe high uric acid is doing that for us as well This is connected to the neuro protection hypothesis There's long been noticed that in many neurodegenerative diseases There's an association at least with low uric acid and some preliminary evidence that in some cases at least adding uric acid or It's a precursor ionicine can Improve outcomes, but I think the jury is still out on whether that's actually the case There is a blood pressure hypothesis so contrary to what you may have heard in all likelihood we probably didn't have very high sodium intakes during most of our evolution and Watanabe and Their group showed that in the context of a low salt diet High uric acid can be really important for maintaining blood pressure Which could have an important role in the transition to bipedalism? But by far the most important and prevalent theory about why we don't have your case is What I'm calling the thrifty pseudo gene hypothesis a pseudo gene is a turned-off gene it comes from Dr. Richard Johnson who is by far the most prominent researcher the most worldwide expert in uric acid. He's obviously very prolific So before we can understand the pseudo gene hypothesis, let's talk a little bit about the thrifty gene hypothesis Forgive me. I spelled James Neal's name wrong. It should be to ease, but he came up with this theory in the 60s And it goes basically like this so in the past we had a lot of famines So it was advantageous to fatten easily so that we could then survive and reproduce during these famines And so we probably had a gene that's making us more likely to fatten And now of course that's a problem because we don't have those famines anymore And so that's the origin of our obesity crisis There have been a lot of criticisms levied against this theory most prominently by John Speakman, but others as well I'll go through a couple of them that relate to this talk So one is This and this one's kind of weak But there is some question about whether how much selective pressure famines really had and whether Some people argue that famines didn't really become a huge problem until after agriculture. That's a question But more important is this survival idea Because in famines the people die of disease not starvation. And so it's unclear that having extra fat would help And more over there are problems with the reproduction idea For example famines tend to affect the very young and the very old not the reproducers and Fertility rates seem to be affected by the incoming signals of fuel availability And it's not clear that just having more fat is going to differentiate there and then another related criticism is that if you look at famines recently Birth rates do fall, but then they're immediately followed by compensating booms And there's no evidence to suggest that it's the fatter people who are creating the fertility booms There's a problem about finding an actual gene that would do this and then finally I just want to mention that We've had some long periods between famines in the recent past And we didn't see anything like the rates of obesity that we have now So if if that was going to happen why didn't it happen then and other questions? Could probably be a whole talk So when I first saw this paper from Rick Johnson in his group that was talking about the Uracase being the thrifty gene or the thrifty pseudo gene I was immediately very skeptical, but it turns out that there are some really good improvements in the specifics of it So for one thing this is we're talking about a pseudo gene that exists not it's not a gene that we haven't been able to find and For another thing the advantage doesn't have to come from intermittent starvation necessarily But only from the reduced ability of fructose and glucose because it turns out that if you eat enough glucose You'll actually start making fructose endogenously So let's talk about the relationship between fructose uric acid and obesity It's been shown that fructose has a unique ability to raise uric acid compared to low fructose and in fact that source of Uric acid has been so well recognized now that this author or these authors put it in terms of the old view and the new view Or the old views said well so much only so much of your serum uric acid can come from diet Because the rest of it's all endogenous and then later we realized oh even that endogenous part can be drastically affected by diet So Johnson and his group with the thrifty gene or a thrifty pseudo gene Hypothesis have what they call the fat switch and it has to do with AMP which comes from use of ATP so when your amp is a Pool gets really high There are two really important pathways that amp can go into and one of them leads to through amp D To fat accumulation and has also this effect of raising uric acid And the other one is through amp K, which actually does the opposite leads to fat utilization and So their great insight is that fructose metabolism results in a huge Influx of amp and not only that it up regulates the amp PD pathway Which can dominate over the amp K and create more fat accumulation and even further than that Some of their research suggests that the uric acid itself can then feed back into it up regulating amp D So you're in this big fat accumulation cycle and Another cool thing about their theory is that they also Incorporate the vitamin C loss into their theory because it turns out that vitamin C at least partially has been shown to Decrease or mitigate that effect of fructose on fat storage and they note that riper fruits have more fructose and less vitamin C and vitamin C Stimulates your excretion so it lowers it and they also note that in Synthesizers if you eat if they eat fructose their synthesis of vitamin C goes down So all of these suggest that even vitamin C might have been an early attempt to raise uric acid So let's compare those then quickly So the the advantage of the thrifty pseudo-dune hypothesis is it doesn't necessarily have to involve famines because it can just involve Availability of flukto fructose and glucose which they did show happened in the time period involved and so They're saying it would be advantageous to fatten easily from that and so we developed these pseudo genes that help us be more sensitive to fructose and We now no longer have that low fructose environment and therefore we are bees One thing I really like about it is it turns the idea from something about you're just eating too much to the quality of the food You're actually eating but or still left with a possible interpretation, right? That high uric acid could be an advantage if you're in that low low fructose environment and a disadvantage now when we're in a high fructose environment And maybe maybe it's actually just a marker for metabolic syndrome One thing I really hoped to do for this talk but didn't have time to do is to do some analysis where you would adjust for some Data and see if reducing uric acid or sorry Adjusting for metabolic syndrome would then show some kind of positive effect, but I didn't have time to do that someone's did some did something similar with cognitive defects or not defects but Dimension of function in old age and dementia they adjusted for CVD risk which is metabolic syndrome, right and they found that when they take that away there was some actual Advantage at least in their data for a decreased risk of dementia So that's interesting But we have to come back to this idea that uric acid itself seems to be causing this ampd dominance and in fact that group suggests or Claims basically that this should be causal of metabolic syndrome and that I don't really have time to go through all of it, but This was an in vitro experiment where they had cells that were starving regular and starving and with uric acid or not and they showed that the starvation effect of upping ampk and Reducing triglycerides and upping beta hydroxybutyrate was abolished basically by adding uric acid. So that's that seems really bad but This doesn't make a lot of sense when you look at the research of uric acid and ketosis So it's long been known that at the beginning of a ketogenic diet or when you're fasting serum uric acid goes way up as a consequence of the clearance going way down and In this same year several papers were published on this topic and I chose this one because it has a need experiment and pretty graphs They showed well They know first of all noticed that the onset of that high uric acid and the reduced clearance is the same as the ketones Going up high and then they showed but that an infusion of beta hydroxybutyrate will also Reduce the uric acid clearance and so this was the beginning of the of our understanding that they compete for reabsorption and clearance in the kidney and I'll just touch on this very briefly you should know that a ketogenic diet that only happens at the beginning it actually writes itself after a keto adaptation so this was a reanalysis of some atkins dieters and if you look at the Results after six months you can see that people who had low or at borderline high uric acid It's the same as baseline after six months Although there's a positive or beneficial effect for people who had hyperurethemia that actually came down So in the long run, it's good for hyperurethemia. So in case you were wondering about that But If we look at this again here, we're seeing a big rise in serum uric acid if this Abolished the ability of AMPK to be dominant and do the policies that we would just die from fasting, right? Obviously in no matter what's happening in vitro. We're definitely becoming AMPK PK dominant during fasting One theory that came out in a paper this year was that it has to do with glycogen stores And what they're trying to show in this diagram is that if you have low glycogen stores Then fructose gets funded into glycogen synthesis and it's even been suggested that that's good for athletes But if your glycogen stores are topped up then only then is the fructose going to go down the fat synthesis pathway Okay, so finally let's look at this from a cross species perspective It turns out there's another set of animals that don't have uricase a Few but birds is one of them and they have very high uric acid For example Here's a peregrine falcon in this experiment their baseline level of uric acid is comparable to humans, right? It's at the high end. It's already six point five milligrams per deciliter after eating a meal of meat Which they normally do It went way up to like Astronomical kind of levels and there's no gout normally in birds of prey The other really interesting thing about them is that in some cases they are also double knockouts So it's not everybody. They've had the uric acid Uricase mutation for a very long time, but some of them in multiple independent lines Also have a vitamin C knockout and that includes Migrating birds forgive me for reading something, but I think this is a beautiful quote The metaphor of marathon running is inadequate to fully capture the magnitude of long-distance Migratory flight of birds in some respects a journey to the moon seems more appropriate Birds have no access to supplementary water or nutrition during a multi-day flight And they must carefully budget their body fat and protein stores to provide both fuel and life support So in other words when birds are migrating they are fasting They are the ultimate cyclic ketogenic Athletes and in fact they are ketogenic when they do this Here's an example of some post-exercise ketosis in birds the levels of beta hydroxybutyrate are pretty high You might not think it's very high because if you think about a human in a similar situation That would also probably be that level, but I've looked at ketosis in a variety of different species And I've never seen that level in humans in any any species other than humans and birds Granted I haven't looked at everything, but for example if you take dogs who do have uricase If you put them in a similar context you would expect about a quarter of that level and they also have high uric acid These are in unfamiliar perhaps units, but we're talking on the low side about 2.5 milligrams per deciliter and on the high side 11.5 and The the authors here we're trying to distinguish between different species and so they did this Principal components analysis saying that there is a negative correlation basically some species of birds rely more on Ketogenesis and some rely more on gluconeogenesis and that that kind of makes sense so the fatter birds are using more lipolysis and That shows up in uric acid because that's a result of proteolysis So what are some different sources of high uric acid? There are the vegan situation which I speculate might be from Excess GNG due to amino acid deficiencies Diabetes we know is a dysregulation that involves excess GNG. So maybe that whole metabolic syndrome Relationship comes down to burning your muscles inappropriately We have tissue damage We have exogenous sources of purine's that get broken down and Then there's only there's only one thing that I know of that has to do with the excretion side And that's that early-stage ketosis where you have the trans shared transporters So I'm gonna say something that's purely speculative. I was thinking about this And I thought well wait a second they're sharing transporters for excretion And we so we know that when there's suddenly a high influx of of ketone bodies the uric acid goes up but what if What if the benefit of high uric acid was to enable higher ketosis? What if the reason that birds and people have so much higher levels of ketosis is actually because they happen to have high uric acid and That keeps the ketones and circulations So it's just a very preliminary hypothesis, but when you look at this figure It's very suggestive because you have you see that uric acid shooting up in the blood and this the ketones shooting up in the blood and the uric acid clearance going down and it kind of Suggests that maybe the clearance of ketones is also similarly impaired in this period so if if uric acid levels lend some benefit and if the largest difference between our Closest primate relatives and us comes from our leaving this hind gut fermenting diet to a diet that's Basically hyper carnivorous very high meat eating so high that some scientists don't know what to make of our isotope levels of animal protein You would you would think that eating a lot of meat would already Raise our uric acid levels so much that you the you would almost think the opposite thing would happen We would lower our ability to retain uric acid to compensate for that, but that hasn't happened So maybe it's possible that the high uric acid that we had boosted our ability to use acute adenic metabolism on our high meat low fructose diet And anyway, that's that's all sheer speculation, and I thank you for letting me say it but even if we don't know What the real advantage is I'm not particularly convinced that the fattening effect is the whole story Because we still have all those problems with fat and as a being fat not necessarily helping with reproduction And we still I think that the question is still open if Fructose and glucose intake is low and glycogen stores are regularly depleted be that through exercise through intermittent fasting or through Periodic ketogenic dieting Is uric acid still a risk factor for metabolic syndrome in some kind of a trade-off manner or is higher uric acid strictly a win? And I I'm really enthusiastic to find out if we can find more experiments that will lead to better understanding So thank you one thing that occurs to me That's not incompatible with with what you're suggesting about ketosis is I I know that urea is which is not the same as uric acid, but is used in the osmotic gradients of the kidneys and Endurance hunting in humans and migratory birds for example There's water conservation is really important and I'm wondering if our high levels of uric acid and tight regulation You're of uric acid might be a water conservation mechanism. I love that idea I I have this suspicion and again, this is speculation that we drink a lot more water than We normally would have and that we probably had a different kind of water and salt Balance than we then we used to Certainly that's that's a big argument in the bird situation with uric acid It's because of the water solubility and there's also something related to having to do excretion while you're still in an egg Which wouldn't obviously That's a really neat suggestion. Thank you as a follow-up on that. Do you have any thoughts about salt on a carnivore diet? Yes, I have a lot of thoughts I Not sure how much since they make but one thing that I've noticed is that a lot of long-term carnivore dieters have spontaneously reduced their salt intake and so I've been thinking a lot about why that might happen and I I'm not sure if it has to do with with again water balance If you you know in the early days of ketogenic diets for epilepsy one of the things that they did particularly was reduce restrict water intake and that that had a Beneficial effect on on sodium and so if if we're eating less or if we're lying more maybe on metabolic water from from fat and Even protein that might have an effect another thing that I learned recently is that if you look at some salt lick Behavior and certain herbivores They will go for salt much more after they've eaten a lot of plants and the idea that the researchers who found this came up with is that Detoxifying the plant compounds actually takes a lot of sodium And so it's possible that actually eating less plants requires less sodium, but I don't know I'm making that all up In your in your research about this did you come across anything and perhaps I missed it at the beginning of your presentation That could anything that would give insight into the mechanisms of gout independent of uric acid or because it seems that this It it seems clear that in some situations high uric acid level may be beneficial It may even serve an antioxidant role or it's competing with BHB things like this It seems that the the equation for gout is more complex than just the elevated uric acid like I learned in medical school So any thoughts about what could be the other piece of that equation? It's high uric acid plus oxidative stress or something else Well, so gout requires that the urate actually crystallizes and once you've got a crystal then that If it's not if it doesn't dissolve again right away, it can it starts to build on itself So that's one problem another problem is that Any changes in in uric acid level up or down? So if you get medication for hyperureosemia that can actually trigger a flare and I think that might have to do with crystals just Coming out again because the because of the levels evening out So now there's more room for uric acid and crystals come out, but they're already crystals, so then it causes another But in terms of like what you could do dieterally. There's you know In terms of stones in the kidneys which have a related kind of problem you can try to Alkalinize your urine and that will help prevent it, but I really don't know I'm not sure. I don't know if that's because it's not known or if I just couldn't find it I've happened. I happened to have done some research on that and What got me interested is long-term fasting your uric acid goes very high But gout patients when they're long-term fasting even though their Uric acid goes very high all their symptoms disappear Well turns out that you have to have another component with uric acid to create gout and Probably the most common one is high blood sugar okay The other which disappears of course when you long-term fast, right and the other thing is High iron you have to have so if you don't have either high iron or High blood sugar You don't get gout if you have high uric acid Fascinating. Thank you. Great Emma. Thank you so much