Protein’s impact on appetite, and uric acid's link to disease & how to manage (AMA 62 sneak peek)

1. 0:00 – 0:12

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia.

   2. SPSpeaker0:11

      Peter, welcome

2. 0:12 – 3:03

   Overview of episode topics (and an important discussion on fanny packs)

   1. SPSpeaker0:12

      to an AMA. How you doing?

   2. PAPeter Attia0:13

      I'm good. Thanks for having me back. By the way, you never comment when I say that, like, "Thanks for having me back."

   3. SPSpeaker0:18

      [laughs] I just-

   4. PAPeter Attia0:20

      Like, it's such a stupid thing to say

   5. SPSpeaker0:22

      ... it's like-

   6. PAPeter Attia0:22

      I don't know why I say it

   7. SPSpeaker0:23

      ... it is, it, it, [laughs] it's just natural probably for you, but yes, it's, it's one of those if you're not here, it's a lot different of an episode, for sure.

   8. PAPeter Attia0:31

      [laughs]

   9. SPSpeaker0:32

      Um, well, speaking of that, before we get into it, there is something that I've been waiting to talk to you about, may or may not have been due to your fashion or lack of fashion choices. Does that help ring another bell?

   10. PAPeter Attia0:45

       Fanny pack.

   11. SPSpeaker0:46

       Yes. Do you wanna let people know what you were rocking and how big that thing was?

   12. PAPeter Attia0:53

       Unless we're planning to do a dedicated AMA on the utility of the fanny pack, I don't know that we wanna go down this rabbit hole.

   13. SPSpeaker1:01

       Are you worried that you have to justify it with a full 90-minute podcast to why you should be wearing that in the first place?

   14. PAPeter Attia1:08

       Well, I mean, north of 25,000 people voted, uh, in disfavor of the fanny pack, which, you know, look, there's... I would bet that the same number of people who think that the fanny pack is a faux pas, um, are probably equal in proportion, not necessarily the same people, but equal in proportion to the number of people who think HRT causes breast cancer or, you know, TRT causes prostate cancer. And so, you know, it, it requires, um, you know, deep, thorough, nuanced discussion to explain the merits of certain approaches, and I think the fanny pack is no exception.

   15. SPSpeaker1:48

       That, that was quite a leap that you made there, which I didn't see coming. The biggest argument against the fanny pack that I saw was a photo where you had the big old fanny pack on and your phone in your pocket. So what's the point of the fanny pack if the phone's not even going in there?

   16. PAPeter Attia2:09

       Uh, that was one photo. For the most part, the phone is in the fanny pack. I think in that moment, the, the phone, out of habit, was just placed back in my pocket.

   17. SPSpeaker2:21

       It was just a weak, weak moment on your part.

   18. PAPeter Attia2:24

       I mean, there is a slight friction to the fanny pack 'cause you have to undo the zipper to put it in and then put it back in, and if you think, "I'm gonna use this phone again in five seconds," sometimes it's just easier to put it in your pocket.

   19. SPSpeaker2:36

       Mm-hmm. Mm-hmm. All right. Well-

   20. PAPeter Attia2:38

       But I, I was very amazed at how many times the fanny pack showed up on social media that I'm not even paying attention to, but somehow you are, and you keep sending me these pictures of me with a fanny pack all over the place.

   21. SPSpeaker2:53

       I mean, it was shocking how much it made the rounds-

   22. PAPeter Attia2:56

       [laughs]

   23. SPSpeaker2:56

       ... and a little alarming as well, but-

   24. PAPeter Attia2:58

       [laughs]

   25. SPSpeaker2:59

       ... that's all right. We'll, we'll save it for another podcast. But for this

3. 3:03 – 10:03

   Understanding uric acid: its role in metabolic processes, its association with gout and kidney stones, its impact on blood pressure, and more

   1. SPSpeaker3:03

      AMA, we're gonna touch on two different topics. The first is one we've spoken about before, but it's been a really long time, and actually since then, a lot of new information has come out, and that's on uric acid, which is a blood-based biomarker. A lot of times when people think about uric acid, they naturally go to gout. However, we'll cover it as it relates to diseases, metrics that you look at for yourself and your patients, and then from there, we'll go into protein, obviously a topic we have covered in great detail. But for this conversation, um, we're gonna cover a piece that we haven't before, and it's something we get asked about a lot, which is the relationship between protein and appetite. And so I think we'll cover some pretty interesting effects of protein and how they're unique to protein compared to other macronutrients on appetite, energy expenditure, and what that means for protein intake, weight control, and how different types of proteins compare within that. So I think it should be a pretty interesting conversation. But with that said, anything else you wanna add before we get started?

   2. PAPeter Attia4:05

      No. I think, um, I think this is a really interesting, um, couple of topics that are also somewhat adjacent in terms of the relationship between protein and uric acid, which obviously we'll discuss.

   3. SPSpeaker4:16

      Yeah. And also, I assume you had a lot of protein in your fanny pack in those photos. Is that correct?

   4. PAPeter Attia4:21

      I, I did. That's one of the beauties of the fanny pack is you can transport protein.

   5. SPSpeaker4:28

      There you go. You should've led with that, and I think people would've been a little more understanding.

   6. PAPeter Attia4:31

      [laughs]

   7. SPSpeaker4:33

      Um, all right. Well, I think it'd be helpful to start off on the uric acid, just reminding people briefly, what is uric acid? Why should people even care about this metric?

   8. PAPeter Attia4:44

      Yeah, so, so great, great question. Look, I think uric acid is probably something that many people have seen on a blood test. Uh, it's not something that is commonly ordered, um, but, but it, it wouldn't surprise me if people have at least seen it once or twice on, on a, on a blood test. Um, and I think the other thing that, that may, um, rouse some familiarity is that people will associate uric acid, uh, correctly with, with gout. Um, but let's just take a step back and talk about what it is. So, so uric acid is a metabolite, right? It is, it is the product of the breakdown of purines. So purines are, um, certain types of DNA and RNA building blocks Um, and as DNA and RNA are broken down, and in particular, these types of building blocks of DNA and RNA referred to as purines are broken down, one of the downstream byproducts of this is uric acid. Uric acid is also a metabolite of fructose. So again, people who have heard us talk about fructose on the podcast before, uh, very specifically with Rick Johnson, who I think has been on twice, if not at least once, um, we talk at length and in great detail about the biochemical pathway that leads from the metabolism of fructose to uric acid. Some people might even remember, um, I, I do write about it in Outlive, where I talk about, um, a particular, uh, mutation in a gene for an enzyme that is quite unique to our species and some very adjacent species that actually, uh, allows us to have higher levels of uric acid than many of our, uh, r- related species ancestors. Um, and I won't go into all the reasons why, but it, it might have to do with a survival advantage that was afforded to us specifically during a period of extreme cold, um, in, in what is now Europe. So all of that to say, uric acid, pretty interesting molecule. Uh, most of our understanding of it, of course, is associated with pathology, and most of that pathology centers around gout. So when uric acid crystallizes, it can do so in joints. And, um, because it is quite inflammatory when it crystallizes, this inflammatory condition within the joints, uh, is what is clinically known as gout. And if you've ever had this, people listening will know it is incredibly painful. Uh, for reasons that are not entirely clear to me, uh, and maybe they're clear to some, uh, the great toe, the big toe, uh, seems to be one of the joints where this occurs disproportionately. Um, and when patients get this, uh, you, you know, you, you, you can ride it out, but more commonly, you actually have to put them on pretty potent anti-inflammatory drugs. Uh, the other place where this shows up is in kidney stones. So while it's not the most common form of kidney stones, um, it's, it's, it's probably number two or number three. And so high levels of uric acid are also gonna predispose, uh, to, to urate-based, um, kidney stones. Finally, I would say, um, and we're gonna go into this in more detail, hyperuricemia, high, high levels of uric acid contribute to high blood pressure. And this has been demonstrated experimentally, and it has been demonstrated through Mendelian randomization. We're gonna talk a lot about Mendelian randomization today. And the reason for it is MR is a really valuable tool for establishing causality when you are studying a biomarker or a phenotype for which there is great genetic variation. So Mendelian randomization has helped us make sense, uh, a- a- although I don't think we need it to make much more sense of the causality of LDL in, um, atherosclerotic cardiovascular disease, right? So all the clinical literature on LDL makes it pretty clear that lowering LDL lowers, uh, cardiovascular disease. But you could ask the question, well, do we know that it's the, you know, that lowering LDL is the cause of the reduction in risk, or is it that giving medications that lower LDL lowers something else like inflammation, and that's the driver? But when you do Mendelian randomization and you look at the genetic distribution of LDL cholesterol, um, you see that, in fact, there is causality. And similarly, when you do that type of analysis with uric acid, you see that, um, as uric acid levels go up, so too does blood pressure. As uric acid levels go down, so too does blood pressure. All of this, of course, is confounded by the fact that things that are bad for you tend to raise uric acid, and that association is a little difficult to, um, tease out causality. So for example, we know that patients with fatty liver disease and patients with type 2 diabetes usually have very high uric acid levels, and it's unclear exactly what the, uh, direction of causality is there. So probably a longer answer than you wanted, Nick, but given, uh, you know, the, the, the nature of, of what we're talking about, it's probably worth giving a bit more of an expansive response.

4. 10:03 – 13:39

   Non-modifiable factors that influence uric acid levels

   1. SPSpeaker10:03

      And if someone's looking at their uric acid levels, what are some factors that can increase their level of uric acid?

   2. PAPeter Attia10:11

      Well, I, I sort of think of this as what are the modifiable things and what are the non-modifiable things. So let's just start with the non-modifiable. Um, so sex is the biggest difference. Um, on average, men have a uric acid level that is about 0.5 to one milligram per deciliter higher than women at a given age. Um, now that's based on the literature. If you asked me personally, like based on my experience and said, "Peter, tell me what you think," I would have said it's easily one to two milligrams per deciliter higher, just based on what I see in patients. Um, so in other words, the, the gap seems even larger to me than, than what is reported in the literature. Um, but, but nevertheless, there, there's, there's clearly a sex difference there. Um, and, um, y- you know, I, I-- the, the most obvious hypothesis is that it centers around estrogen, uh, and some of the downstream effects of estrogen. Uh, it's also clear, by the way, that not only do women tend to have lower levels of uric acid, they also seem to be more susceptible to higher levels or to a given level of uric acid. In other words, they seem to be, uh, more likely to run into the trouble of a high uric acid, uh, than a man is at a given level. Okay. Um, the other thing, I alluded to this also above, is genetics. Uh, the heritability of uric acid seems to be about forty percent. In other words, nearly half of the value of your uric acid is determined genetically. Um, and that means independent of just sex, but I'm-- you know, let's just say across men or across women. And again, um, that genetic variability, that heritability of uric acid is actually what allows us to determine the causality of uric acid in so many of these things that we care about. If there was no genetic variation to, um, to uric acid, it would be very difficult to do Mendelian randomization. The, the next thing that's not modifiable that plays a significant role in uric acid is age. And, uh, as we increase in age, we tend to increase in uric acid, although this effect is more pronounced in women than men, and it starts around the age of menopause, which again factors into the hypothesis I alluded to earlier, which is that estrogen probably plays a significant role in uric acid, uh, regulation given that women are lower and then tend to have a big uptick, uh, when they get through menopause. So, um, actually, there's a pretty cool figure that might be worth showing for, for folks if they want to see the relationship between uric acid in men, women, and then what happens around menopause. So, um, Nick, if you can just pull that up. Um, this is a figure that really speaks for itself here. Um, obviously, the blue line represents men and the red line represents women, and you can see that the blue line kind of, you know, is-- well, first of all, it's always higher than the red line, and the rate of increase is modest and steady. Uh, conversely, the red line stays largely flat until the mid-forties and then really increases at a rate that exceeds even the rate at which the males increase. And this continues throughout life. But to note, even at the age of eighty, which is where these data stop, women are still, uh, considerably lower than men.

5. 13:39 – 20:05

   Modifiable factors that influence uric acid levels

   1. SPSpeaker13:39

      And so you kind of laid out those are the things that people really don't have control over. What do we know about factors that can cause uric acid to raise that people may have control over?

   2. PAPeter Attia13:51

      Well, a, a lot of discussion on this topic kind of points towards nutrition because epidemiologic data tell us that, um, average serum uric acid levels have been increasing pretty substantially over the past century. So in addition to all of the things that we've talked about, the sex differences, the age progression, if you just look at the population level of uric acid, it is going up. Um, and therefore, the obvious question is, is it going up, um, for the same reasons that certain other things are going up, such as obesity and metabolic syndrome? And if so, what is it about those things that's increasing uric acid? Well, given that fructose is one of the things that drives, um, uric acid production, at least transiently, the question is, does chronic consumption of high amounts of fructose, presumably in liquid form more than solid form, play a role in this? Does it play a role directly, or does it play a role indirectly? What does that mean? Well, directly would mean does fructose consumption, which is known to and unequivocally increase, uh, uric acid levels transiently, does enough fructose consumption lead to chronic elevation of uric acid? That's, that, that I think is an unknown question. Um, an alternative explanation is that high levels of fructose consumption are driving more eating, right? So we talked a lot about that with Rick Johnson. What is it about fructose consumption and intracellular energy levels that lead to more consumption of food and therefore, uh, obesity, and is that the driver, uh, through, through energy balance? So, um, y-you know, there, th-there, there have been bidirectional, uh, Mendelian randomization studies that have been done, and they have suggested that higher levels of adiposity can cause hyperuricemia. Uh, so in other words, that would explain that, um, that, that, um, that, that obesity and energy imbalance is a driver of elevated uric acid and not the other way around. By the way, that's, that's done by looking at, um, genes that are known to increase fat mass, such as the FTO gene, uh, MCR, uh, uh, MC4R gene, and other genes that are, um, clearly associated causally with obesity. Um, there are certain medications that can do this, so diuretics, which are very common in the treatment of, of high blood pressure, and even low dose aspirin can do this. Uh, again, we talked about obviously the, the dietary effects of fructose, but we shouldn't, uh, negate the dietary consumption, uh, of foods that are very high in purines. So foods that are very high in DNA, meat, uh, and believe it or not, beer is quite high in DNA. Why? Because beer contains a lot of yeast, and, um, the yeast obviously has genetic material in it. So high amounts of alcohol, though again, I think disproportionately beer over other types of alcohol, uh, high amounts of very dense food. So sar-- you know, uh, by foods, I mean foods that are dense in DNA, so sardines, uh, and things of that nature, and red meat. These are things that are going to also, uh, increase the, the production of uric acid. Now, I'll tell you about another funny example, Nick, of something that I learned many years ago when I was in ketosis, which is that, uh, being in ketosis, either nutritionally or through starvation, um, will increase uric acid levels and can do so quite dramatically. And the reason for that is the primary ketone that is produced during either of those states, nutritional ketosis or starvation ketosis, i.e. fasting, uh, is something called beta-hydroxybutyrate. And beta-hydroxybutyrate competes with uric acid, uh, in the kidney for the same transporter that is going to, uh, excrete either uric acid or BHB. So when BHB is outcompeting uric acid, uh, vis-a-vis, you know, impairing this tubular, uh, secretion in the kidney, uh, uric acid is going to go up. And so the first time I learned that was when I was deep in nutritional ketosis and I actually got gout, and this was probably 12 years ago. Um, and because I didn't fit the phenotype of gout, right, at the time, I was just, you know, really lean, really healthy, you know, smoking and joking in my ketosis, it took me, like, two weeks to figure out why my toe hurt so much that I couldn't do a flip turn in the pool and put any weight on that foot as I pushed off. I mean, that's how bad it was. Um, of, of course, I would go on to learn exactly what happened, and then in subsequent years, as I would fast, um, I would always make sure I was taking allopurinol or something. But I did confirm that during some significant fasts, my uric acid would rise from, say, five to nine or 10 as my ketone levels approached, you know, four and five, uh, millimole. So, um, those are, those are some of the things that, that are, you know, modifiable and, and obviously, uh, play a role. One other thing that's, by the way, kind of interesting, uh, is, uh, anaerobic exercise, uh, like heavy, heavy bouts of anaerobic exercise can also increase uric acid transiently. Um, it, it might be that this goes away over time, um, but, um, we're not entirely clear why. The hypothesis is that high doses or, or rather heavy bouts of anaerobic exercise cause depletion of muscle ATP and that the energy needs of the muscle obviously can't be met exclusively by glycolysis. So, um, it, y- you know, we basically, uh, experience the buildup of ATP degradation byproducts in the muscle, uh, and in particular, one of those is IMP, uh, which is converted into uric acid. So, um, uh, I, I think what's interesting is that there seems to be an adaptation to that, um, and I'm also not convinced that there's anything pathologic about that. So that, that's just more of an interesting aside, not like, oh, don't do, don't do intense anaerobic activity.

6. 20:05 – 23:30

   Association between high uric acid levels and cardiovascular disease

   1. SPSpeaker20:05

      And you mentioned kinda earlier a few times the relationship between uric acid and blood pressure, and we know about blood pressure's role in cardiovascular disease. What do we know about uric acid as it potentially relates to the risk of cardiovascular disease?

   2. PAPeter Attia20:23

      Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. So if you wanna take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode, and the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything, or AMA, episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic, and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, the Qualies, an additional member-only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you wanna learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of all disclosures. [outro music]

Episode duration: 23:30