Blood Chemistry in Athletes [transcript]

Written by Christopher Kelly

Nov. 7, 2018

[0:00:00]

Christopher:    Hello and welcome to the Nourish Balance Thrive podcast. My name is Christopher Kelly, and today I am delighted to be joined in person by Dr. Tommy Woods. Say hi, Tommy.

Tommy:    Hi, Tommy.

Christopher:    Oh, dammit.

Tommy:    Every time.

Christopher:    Yeah, I didn't spend long enough thinking about that before I asked the question. Today we are going to be talking about blood chemistry and some specific changes that we've been seeing in the athletes that we've been working with, whether or not they represent something that we should be worried about or something that represents training benefit that's going on or what might be going on here because this is something that we're seeing quite a lot.

    Just to take a step back and give you the bigger picture, at Nourish Balance Thrive, we run this Elite Performance Program, and it's a coaching program that involves doing testing and that testing is blood chemistry, and we do a urine analysis, organic acids, we do stool testing, we do all kinds of different tests, but we always start with blood and we track with blood.

    The nice thing about blood is it's ubiquitous, it's fairly inexpensive, we can do it, basically, as often as you like during the program and see some changes. So we have the most data using blood chemistry, and often we see some surprising results that don't make a lot of sense and sometimes we have to explain that to the client who also may be explaining them as a patient to their doctor.

    So let's start with talking about the liver enzymes, ALT and AST and maybe GGT and the changes that you might see after you do a hard workout because that's the classic one we've got some explaining to do to the doctor. Do I need to refer you for a liver ultrasound or something like that? So can you talk about some of the changes that you might see after a hard workout in your liver enzymes?

Tommy:    Yeah, the simplest answer is that they go up.

Christopher:    That's it.

Tommy:    Both AST and ALT, and they have slightly different periods of time in which they come down, but after three to seven days, you'd expect them to normalize in most people. It might be faster in some than others, but that would typically be an normal period of time. So if you had a particularly hard workout, maybe you went CrossFit or you did some German Volume Training or had a hard interval session on the bike or something like that and then you tested your liver enzymes the next day and you're surprised that they're more elevated than usual, it might just be that you had a hard workout the day before. Equally, if you look at something like GGT, that shouldn't change too much. That's usually more stable.

    When you're looking at things like ALT and AST, you might be thinking about things that cause inflammation of the liver, hepatitis, [0:02:31] [Indiscernible] and autoimmune diseases, fatty liver, those certainly go up with that too. If those things are on their way up consistently then that is something worth investigating, liver ultrasound or something similar, possibly have a look at your liver, but if it's just an acute thing that's just the result of a hard workout then that's probably something that's less worrying. So just knowing where you are in relation to a hard workout is something that you should discuss with your doctor if these things come up.

    Equally, I think we have a few people who always write off elevated liver enzymes as, oh, because I worked really hard in the gym the other day, but if it's consistently elevated, that's also worth investigating sometimes. So just because something has increased in one particular scenario, don't necessarily use that as a reason to always write off something that's maybe worth looking at.

Christopher:    So these transaminase enzymes, they normally live inside of cells, right, so when they become elevated in the blood, that means something happened to that cell. Correct?

Tommy:    Yeah, not necessarily actually. So you'll see an increase in ALT and AST and something like -- so you're seeing Type 2 diabetes. Traditionally, people thought that the reason it was going up is because the liver was being damaged, and these enzymes were being released from the cells, but actually it's the case that he liver is just making more of these enzymes. It's partly to do with probably unregulated gluconeogenesis in the liver, and you want more ALT to help do that. Then because it's more in the liver that you just end up seeing more in the blood.

    So, in terms of the acute effects of exercise, I don't think the exercise is directly causing liver damage, but in that period of time, if you're asking for that metabolic shift particularly during an intense exercise, I think that that might just be part of an up-regulated enzyme production from the liver. It's obviously possible that you can get dramatic decreases in flow to the liver if you do really intense exercise and all of your blood is being diverted away from the abdomen to exercising muscles, but it's very unlikely that you're causing large amounts of direct liver damage. It's probably a shift in metabolism, an up-regulation of enzyme production like you get in some disease processes.

Christopher:    Our reference ranges for the transaminase enzymes, ALT and AST, are very different from the standard reference range that you'll see on your raw data if you look at that from Quest or LabCorp or wherever you got your blood test done. Can you talk about why our optimal range is different from standard reference range?

[0:05:01]

Tommy:    Both of them, ALT and AST, the top of our optimal range is about half of the top of the normal range.

Christopher:    That's quite significant data.

Tommy:    ALT, the top of the normal range is 44 and then the optimal range is 22. AST, the top of the normal range -- and it depends from lab to lab. If your lab is different, that's fine. It's just based on how they measure these things and the reference population that they've used -- so the top of the AST optimal range is 26.

    When you're looking at ways to figure out what's best in terms of a reference marker -- and this is something we've talked about a lot when we talked about the blood chemistry calculators. What's your outcome? Just because the results are normally distributed and if you take results from, say, ALT and it's seven to 44, that fits 95% of the population of people taking the test. That doesn't necessarily mean that you're at optimal when you're within that range. There's still going to be a sliding scale of outcomes within that range because most of the population is fat and sick and dying, generally, so if you want to be normal, in most cases you probably don't.

    When we've looked at this, often things like all-cause mortality, they will come out as ways to objectively figure out a way you might want to be within that reference range. That's why the optimal range is tighter because people tend to have better health outcomes when they're within that range. However, it's certainly going to depend on a lot of things like ethnicity.

    If you're looking at the liver enzymes, in general, somebody who is Caucasian can have ALT and AST much higher than that, could be into 50, 60, 70, 80, without seeing any real change in an objective marker like mortality. However, if you're somebody of Asian heritage, there's a lot of South Korean data, some Chinese data, then as your ALT and AST head up into the 30s, already you start seeing increased risk of various diseases. It's certainly going to depend on things like ethnicity. That's going to be a big part of it.

    In general, if you're looking at the whole population and we try and create something that describes what's best for as many people as possible then those ranges certainly would be it. We would rather that they be a bit tighter, and that causes us to look deeper and say, "Who is this person? What are they doing?" Rather than just saying, "Oh, well, you're in the normal range, don't worry about it."

Christopher:    What does it say to you about the effects of exercise? If we know that people have worse health outcomes when their enzymes are up in the 50, 60 range and that's what happens when you exercise, what does it tell you about exercise?

Tommy:    Yeah, well, it's probably that's part of the stress of exercise. It appears to be part of that autonomic response. You say the same thing about various inflammatory markers, various oxidative stress markers. If you looked at the person straight after that period of exercise and think, this person is inflamed or their glutathione is depleted, their liver enzymes are elevated, this is the person who is on the road to Type 2 diabetes and heart attack, but all of that is part of stressing the system such that it's more robust in the future. That elevation of enzymes may well be part of it.

Christopher:    Do you think that people should, at some point, wait -- so we can link to some studies that have shown that these enzymes do return to baseline after a period of, you just said, four to six days, but I thought I've seen some other studies that show ten days, pretty much everybody is back to baseline. Do you think it's a good idea for athletes, at some point, to wait, say, ten days and do a blood chemistry and make sure that those enzymes are returning inside of the optimal reference range?

Tommy:    It's an interesting question and something that we've actually debated quite a bit. Probably the best answer is it depends. In reality, if it's a liver marker or any other marker that you're worried about following up on in terms of some of the tests, like, is there something going on with my liver, and I need to go and see a hepatologist or a gastroenterologist to go and find out what's going on, get further testing, get imaging, then I would wait and retest.

    If you are trying to just get a baseline look at your health, what you want to probably check is how you look most of the time. How you look most of the time is maybe one day, post-workout, so knowing what state your body is in most of the time is probably going to be more beneficial than gaming the system by waiting for a few days. If you're constantly running high level liver enzymes because you're constantly working out really, really hard and there's no adaptation and you're constantly seeing that increase, maybe that's the reason to then back off your training or look at your training volume or how your training intensity is a split. That's going to be an important part of it too. I imagine that if you go onto that scenario, you'd start to see other stuff come down too. Maybe the sex hormones start to look a bit wonky or the thyroid starts to look a bit wonky because you're just pushing those systems too hard, too frequently.

Christopher:    I remember there being a great deal of individual variability in this response. Some people are, smash it, not going to see anything, and some people just need to look at a barbell and suddenly their AST is 75 or something.

[0:10:09]

Tommy:    That's going to be the same with everything is that there's a lot of personal variability in responses to all of these things. That's part of the benefit of looking inside is that you know where your body lies on that spectrum. I don't think we have any reason to say that having a bigger or smaller response is a good thing or a bad thing. It's just saying you don't have to be really sore after exercise for it to have been a good workout that gives you the stimulus to build muscle or create adaptations. We know there's some variability. As far as we know, that's not necessarily a bad thing or anything you need to worry about.

Christopher:    What about creatinine?

Tommy:    Yeah, creatinine is a pretty good marker of muscle mass, in general. It's used as a marker to kidney function but also is a pretty good marker of muscle mass. That's because every time you phosporylate creatine, there's an error in the process and creatinine gets produced and then that gets secreted by the kidneys. So the more muscle you have and potentially the more active that muscle is, which is generally more [0:11:00] [Indiscernible] which is absolute muscle mass, the more creatine you're making, the more creatine you're rephosphorylating and then the more of that process is going on then it's just more creatinine circulating.

    If you have kidney function issues then you're not clearing that creatinine, your creatinine will go up in the blood, and that's sort of a marker of kidney function. Assuming that your kidneys are working properly, creatinine is a pretty good proxy for some idea what somebody's muscle mass is. I remember when we were in a hospital with -- you have a little old lady who has had a fall and you look at her creatinine and you expect it to be -- it's just super low because she has no muscle mass quite when she fell. The one caveat to that is that you might end up going above even the normal range of creatinine. I've seen that in a few people. If you have reasonable muscle mass and you're taking creatine because creatine just increases that whole process to increase the production to that.

Christopher:    Would you recommend creatine in general for the athletes?

Tommy:    Yeah, in general, I probably would. I think most people, if you're doing any kind of strength-based training, creatine gives an ergogenic effect. There are some people who don't respond to it and that might be relative to methylation function and things like that or it could be something else entirely, that's just our hypothesis, but supporting that process, because creatine is very methylation-intensive, and can have a number of other benefits.

    I was talking to Greg Potter on the humanOS podcast just this morning, and he was asking about creatine as a neuroprotective agent. We know that creatine can be neuroprotective particularly in an acute injury. It certainly works that way in animal models. If you're riding a bike or playing football or soccer or whatever and you get a knock on the head, if you've been taking creatine, maybe there's a benefit there too. So it's very safe. It has been given to pretty much any population in large doses and never really shown to have any problems. So it's definitely a low-risk, high-potential benefit supplement to take.

Christopher:    Let's just clarify here, so first of all we were talking about creatinine which is something that you measure in the blood and then we started talking about creatine which is the white powder that bodybuilders take as a supplement.

Tommy:    Yeah, exactly, take it from a vial and inject it into your buttocks, something else.

Christopher:    Creatine is one of the few supplements that I take regularly, and I've seen huge increases in my sprint power which is super helpful for cyclocross because it's just a series of short sprints. I wish somebody would make some that didn't taste like ass. Well, it doesn't really taste of anything, but it's really gritty.

Tommy:    Yeah, so gritty and slightly bitter, but the thing is the main type of creatine, if people haven't tried it before, buy creatine monohydrate. There are lots of fancy types of creatine that probably don't make any difference, and buy something called Creapure Creatine which is basically by one company in Germany, just pretty much bought from them and then white labeled by every supplement company in the world, so it's pretty much the same from all the companies. Some of them will do extra testing, so Douglas Labs or Thorne might do some extra batch testing just to make sure of the purity but it's otherwise pretty much the same. Yeah, that's the one that we know works and it's the one that has been loads of research. It just, it doesn't taste great.

Christopher:    For our machine learning model of biological age, this is an interesting problem, I think. I'm not sure this has been done too much either in biology or in machine learning. We're trying to predict somebody's age which, on the face of it, it seems like a silly thing to do because I know how old you are. I just need to look at your birth certificate and tell me how old you are. Normally in machine learning, what you're trying to do is predict something you don't know like how much of a risk somebody is for a loan or how much of an insurance premium you should charge them or what the weather is going to be like on Wednesday, things you don't know.

    We're trying to predict something that you do know and we're doing that using a basic blood chemistry. These are 39 input markers that you can get for about $50 from labs like LabCorp and Quest, and we're trying to use those markers to predict somebody's age. The reason we're doing that is so that we can look inside of the model and get an explanation for that predicted age. It turns out that creatinine, the marker that you measure in the blood, is very important for predicting your biological age.

[0:15:11]

    In this case, and this is not true for every single marker that the model thought was important, but for creatinine, there's a very logical, physiological explanation why that might be important, and that is that muscle mass generally goes down with age. That's something, as an athlete or any person listening to this podcast, you're probably going to want to prevent. Correct?

Tommy:    Absolutely, we know both muscle mass and muscle strength, especially muscle strength but muscle mass to a degree, predict longevity and the more you have, essentially, the lower your risk of most chronic diseases. Of course, if you've pharmacologically enhanced that process that [0:15:47] [Indiscernible] issues, but in terms of natural muscle function and production, I believe, if you look at the models, creatinine has a U-shaped curve if you're predicting age.

    If you have very low creatinine, that makes you look older than you are and that's as you get older, you lose muscle mass. Equally, if your creatinine is very high, also makes you old too probably because there are some people where creatinine goes really high because their kidneys fail as they start to get older. Elsewhere, in the middle, it seems to be that having more muscle mass is probably going to lead to more creatinine and that's why high creatinine makes you look young.

Christopher:    I think the vast majority of people here are probably going to fall into that low creatinine -- actually I don't know that but certainly the endurance athletes, right? That's the one thing that we worry about working with endurance athletes, and it's something that I've worried about for myself is you do all of this endurance activity and it tends to lose muscle mass, in particular the fast-twitch fibers that we care so much about for maintaining our balance.

    I don't think people listening to this are going to see elevated creatinine due to poor kidney function. You have to lose a lot of kidney function before you start to see it.

Tommy:    Yeah, you have to lose more than 50%, probably close to 70% of kidney function before creatinine starts to go up, so that's very unlikely. It's more likely that people are going to be on the lower end because of lower muscle mass if they're an endurance athlete.

    Reminds me, we're just talking about somebody who we emailed yesterday, commented on the fact that if you look at his training program, he doesn't have a leg day but he has bicep and shoulder days and all that stuff. He said that his leg day is cycling on the spinning bike and he works really hard on the spinning bike and therefore he has worked his legs hard.

    Sadly, if you're a chronic endurance athlete and the only work your legs get is spinning on a bike then you're going to lose all those important Type 2 muscle fibers and all that kind of stuff anyway so at some point you just have to do some squats, I'm afraid.

Christopher:    I saw a really fun picture the other day, and I forget the names of the two cyclists. Basically one of them was one of the top sprinters in the world of cycling.

Tommy:    Yeah, that Germany guy whose, I can't remember his name, but his quads are ridiculous. We'll have to find the photo and [0:17:45] [Indiscernible].

Christopher:    Yeah, I'll find that photo and link it to the show notes but, yeah, next to one of the climbers. I would like to say what the climber's leg looks like when you're there in person. Relative to the sprinter's leg, they were like twigs. I can certainly post a picture of my legs as testimony that no amount of cycling is going to bear with you a nicer appearance. It just doesn't work like that. At some point you really do have to lift something heavy.

    Let's talk about hematocrit. That's another interesting one especially for the endurance exercise athletes. We know the oxygen deliverability is going to be a key determiner of exercise performance and so a greater hematocrit may be beneficial for exercise performance, but there are so many caveats with hematocrit.

Tommy:    We certainly know -- so, hematocrit testing is one of a big part of the early stages of catching out blood dopers or people who are taking something like EPO to boost red blood cell production and that was if you've ever seen the program which is the -- or read the book which I can't remember the name of right now, probably by Leipheimer.

Christopher:    I've not read that book.

Tommy:    Yeah, it's really good, so about blood doping in the Tour de France and in professional cycling. Basically, they're both about the same thing, the period of Lance Armstrong and the US Postal team. They take all these various things to increase their red blood cell availability then when somebody comes to test -- they use to do hematocrit testing to test the blood for dopers, and they'd be there, trying to push IVs into their blood to dilute their blood down before it gets tested by the drug testers.

    We know the higher your hematocrit, essentially the higher your wattage you output. Your functional threshold power will be higher, you can generate more watts per kilo if you have higher hematocrit.

Christopher:     We're talking about a different energy system now. Before you were talking about creatine which is a very rapid energy source that doesn't last very long. Ten seconds and you're done.

Tommy:    And requires no oxygen whereas if you're talking about oxygen deliverability and long-term power thresholds you would need as an endurance athlete, the higher your hematocrit, the faster you go. That has been well-demonstrated, but if you do a lot of endurance exercise, particularly running, there seems to be a decrease in hematocrit and nobody can quite figure out what it is, whether it's the force of the striking in the foot is directly damaging red blood cells or it's more of an inflammatory because it's higher impact and that's affecting the red blood cells in some way.

[0:20:05]

    Then there's also the volume expansion. You do a lot of aerobic exercise. That can cause a dilutionary effect. There's also an effect of, of intermittent exercise, to then activate hepcidin which then decreases total or tries to decrease total iron source and decrease red blood cell production. There are some adaptations that may actually cause what looks like an anemia or a decrease in hematocrit. In endurance athletes, they seem to [0:20:31] [Indiscernible] the adaptation toward a lot of endurance exercise. Now that doesn't necessarily mean it's a good thing. Perhaps it's too much of a good thing.

    Actually if you're seeing your hematocrit drop quite a lot and you do a lot of high-volume endurance exercise, again, that's one of those things that maybe you turn around and say, well, am I doing too much of this? Because if you could train in a smarter manner and you see fewer of those adaptations, could they allow you then to go faster because then you're not pushing the system so hard? That's always something that's worth thinking about.

    There are also a lot of other things that could be going on. We know that when we start to fix people's guts or deal with some issues with oxidative stress or other exposures then, often, their hematocrit comes up half a point or a point.

Christopher:    I've seen that with iron overload, right?

Tommy:    Yeah.

Christopher:    It's paradoxical, get rid of some iron or even get rid of some whole blood and your hemoglobin and hematocrit end up increasing because you've moved some sort of inflammatory burden.

Tommy:    Yeah, and we used to think that it was just removing the inflammatory burden of iron but then Bryan made a good point which is there's a whole lot of other crap in your blood that if you have some kind of exposure, maybe there's something in there that you are benefited for off-loading by, donated -- and that's only possible. We don't know if it is possible.

Christopher:    Could decreased hematocrit be mediated, certainly men and maybe women as well, by decreasing testosterone? That accounts for the difference in hematocrit in men and women is the level of testosterone and certainly we see that in some of our non-tested, non-competing people that we're working with. They're using some exogenous testosterone and with it comes increased hemoglobin and hematocrit and that's mediated through testosterone, right?

Tommy:    That's a good point. Your testosterone level has, up to a point, a pretty significant effect on your hemoglobin production. If you are, again, over-training, under-eating, poorly recovering, whatever you want to call it, or any of that cluster of lifestyle practices along with being a hardworking athlete, your testosterone drops and that could be causing a decrease in your hemoglobin. So that could be part of it too is that, again, a lot of these may be happening because you're doing too much and not recovering properly. Then if your stressing the system, the body is going to punish you for that because red blood cell production is energetically intense process.

Christopher:    It's a long-term building project, right?

Tommy:    It's a long-term building project, and you don't want to do more of it than you have to. If you're training the body and you don't necessarily have the resources to continue doing that then it will try and turn that system down. So, yeah, that's absolutely another reason why, low testosterone is one reason why hematocrit might decrease. Then if you manage to improve it by improving all those lifestyle factors or health factors or if you end up having to supplement for whatever reason then you'll often see that hematocrit go back up.

Christopher:     Where else would you look on a basic blood chemistry to know whether your level of red blood cells is good? We mentioned the hematocrit has these caveats, faster expansion. Where else would you look on a blood chemistry to see whether or not low hematocrit is truly a problem?

Tommy:    The other two main places that I look are MCV and RDW if you're looking at red blood cells. MCV is the average blood cell size. If they're on a smaller size to maybe below 85 or below 80 then you know it's probably an iron issue or a toxic exposure that affects iron handling.

Christopher:    Or copper, right, it can sometimes --

Tommy:    Yeah, exactly.

Christopher:    -- macerate.

Tommy:    Copper deficiency looks almost exactly like iron deficiency because it stops you absorbing it.

Christopher:    Right, you need to move the iron into the usable form, and that requires copper.

Tommy:    Yeah, exactly, and then if MCV is higher than expected, higher than 90 then you're probably looking at some other deficiency, folate and B12 are most common, but it can also be things like B6. So that gives you a rough idea but then the RDW is another important -- and you could have an increase in MCV if you have a lot of immature red blood cells, so if you're making a lot of new red blood cells. So if you've done something recently, and it will be the same with the RDW, if you've done something recently that then improves your erythropoiesis, improves your ability to make red blood cells, while those red blood cells are being made, they get released into the circulation and not all of them have jettisoned the nucleus so they're slightly bigger. So then if you have more reticulocytes, immature red blood cells, that can actually elevate your MCV and elevate your RDW if you're looking at processes.

Christopher:    Yeah, so maybe worth adding -- I mean, it's a $5 marker to add reticulocytes to your basic blood chemistry. It turns out their quite predictable with machine learning algorithm for five bucks. I mean, it's a personal choice.

Tommy:    It's a good idea. Also because if you're damaging a lot of your red blood cells, for whatever reason, you might see elevated reticulocytes to your body, just continuously trying to catch up with the red blood cells that are being lost because of increased oxidative stress or issues with glucose handling and glycated red blood cells and all that kind of stuff which can certainly happen too. Reticulocytes are nice markers for how hard your body is having to work to keep the number of red blood cells that it has.

[0:25:18]

Christopher:    Given what you've seen us do, what would you think my chances of being able to predict somebody who is blood doping or not, given my machine learning techniques? If you gave me a big data set, say, whoever it is that has been collecting a biological passport from each athlete for years and then they've got the ground truth which is, did you get caught with doping or not?

Tommy:    I would be surprised if that wasn't really easy.

Christopher:    It would be really, really easy and then how would you game it? You wouldn't even know how to game --

Tommy:    Yeah, because you don't know what the pattern is.

Christopher:    Yeah.

Tommy:    Sometimes it's impossible to figure out why one marker predicts something because on its own, it doesn't tell you anything.

Christopher:    No, that's right, it's this really complex model. That would be amazing. What would we have to do to get access to that data to build that model? I don't know. I wouldn't even know where to go.

Tommy:    Maybe Grigory Rodchenkov still has access to some of the -- you could get maybe access to some Russian athlete data and just assume that they've all doped, and that's your ground truth.

Christopher:    If country code equals then doping equals fine. Maybe someone listening could put us in touch with the World Anti-Doping Association or something.

Tommy:    Nikki Keay who was in the podcast recently, she used to work with some of the guys doing that. I think most of them have wrapped up their association with that.

Christopher:    Okay, let's talk about BUN. So this is another important feature for predicting biological age. At the moment, we have more questions than answers but sure as hell do we see elevated BUN in all of our athletes, especially the endurance athletes. Do you want to talk about what the hell is BUN? Where does it come from?

Tommy:    BUN is basically blood urea nitrogen. Urea is the end process of stripping the nitrogen off proteins, amino acids to then excrete them, excrete the excess, and you can measure that in the blood. That's normally peed out but it's a continuous process so you can measure it in the blood. It can be a marker of things like hydration. If you're dehydrated, your BUN can go up.

    In our model, in our predicted age model, there's a point that's very low down in terms of the BUN normal range. Basically the higher your BUN, the higher your predicted age. Then we have to think about why that might be the case, and we know that a lot of people, the people that we see the biggest discrepancy between predicted and biological age, is the high-volume endurance athletes.

    That podcast with Tamsin Lewis. She's a good friend of ours, a doctor in the UK. She was an Ironman UK champion a few years ago. Her predicted age is about double her chronological age, if not more, and one of the things is an elevated BUN. So it could feasibly be dehydration, but it's unlikely; could be increased protein intake, that's certainly part of it, how much protein you're eating. The other thing that I wonder about, and there could be some physiological adaptation that we don't really necessarily understand, I think that's part of where we are currently.

    Again, when you look at say the muscular changes in an endurance athlete, so like a marathon runner or a Tour de France cyclist, they look a lot like this old, decrepit muscle that you get in these sarcopenic old people. They have high intramuscular triglycerides, they've lost a lot of the Type 2 muscle fibers. Of course there are some biochemical differences but, cross-sectionally, they look similar.

    I wonder if there's this element of really high-volume, long-term endurance exercise that causes some of these adaptations that end up potentially being detrimental, and that's what we're picking up. Equally, it could be a beneficial adaptation in the endurance athlete so the model looks a lot like somebody who is old but isn't necessarily a bad thing. That's perfectly possible, and that's something that we have to figure out.

    There could be this increased catabolic state, so if you're breaking down a lot of your protein then you'd expect BUN to go up as well, and thinking about a lot of the endurance athletes that we know, they may be doing a very high volume of exercise which could cause the breakdown of muscle tissue. They may also be under-eating which is likely which could also lead to break down your own muscle tissue. So maybe that's just increasing the amount of protein turnover that's going on. It could just be a marker of that but at the moment, the way it looks, is the BUN and other things point to this potential that this high-volume endurance exercise is causing premature aging, and we're actually just picking that up on the blood test.

Christopher:    At the moment, certainly with BUN, there are more questions than answers, but that's really the purpose of building this model is to try and understand the explanation. We were talking about this earlier. Science is not about eureka moments. It's about, oh, that's funny, what's that about? It can send your research off in a different direction. Has anyone seen this before?

    We've actually seen it as well in the predicted age model with the liver enzymes. That seems to be, for the moment, stay tuned. You might hear from us in two weeks' time, we've figured this out, but there's a paradox with ALT where, as it goes up, the model thinks you're younger. We've really yet to figure that out, why that might be the case.

[0:30:14]

Tommy:    It has been the case in two fairly large data sets, both on athletic and on non-athletic one. We really can't figure out why. Within the normal range or within our optimal range, particularly, and just above the normal range, higher liver enzymes are associated with a higher age, but once you go above the normal range, it seems to think that the higher your liver enzymes are, particularly ALT, the younger you are. If you look at ALT versus age, there's no correlation whatsoever, so there's some really complex relationship in the model with other markers that we don't quite understand yet that says that if you have really elevated liver enzymes, all of a sudden it thinks you look younger.

Christopher:    There are things that you can find that have great utility. As you mentioned, if you see somebody with an MCV of 102 then you know something is going on, and that needs to be investigated and explained fully. It's probably a nutritional deficiency, maybe hypothyroidism, probably all of the above.

Tommy:    There are a number of things that we can pick up in the predicted age model that we can intervene on. An RDW, an MCV, are two great examples that we know the factors that control those markers and we know that we can intervene and change this. We know the nutrients that we can supplement to change MCV which often changes RDW.

    There are a lot of factors that change with the increase red blood cell production, but a lot of those, we have a handle on and we could look at a specific person and say, "Okay, you probably need to do less of this and more of this or maybe you need some more iron or more B12." All of that is going to bring down those markers back, close to the normal range and then that's going to be your predicted age.

    We know also that those markers correlate very well with mortality so basically, the higher your RDW is, the less time you have left to live such that the normal range is less than 13 probably or optimal range less than 13, normal range maybe goes up close to 14, depending on the lab. For each percentage point it goes up, your risk of mortality basically goes up by one too, so it doubles then triples then quadruples. By the time your RDW is 17, which is really high, 17%, you have an eightfold increased risk of mortality. It's really quite significant.

    That's something where we could look at and say this is something that we can really intervene on, and it might not be nutritional. It could be inflammatory or something else going on, but it's something that we know what causes it to be elevated and then we can figure out what that is in a specific person and intervene.

Christopher:    It's amazing you can get so much information from just a basic blood chemistry. I always thought that this was the case. Even back in 2008 and my primary care doctor is running this basic blood test and not saying anything about it just because the numbers were inside of the normal range. Even if they were outside of the normal range, he still would brush it off as, it's not too bad, don't worry about that too much. Not even really taking the time to explain what the marker meant.

    As an engineer, I'm looking at it and thinking, there has to be information here that I'm not using. When you look at other industries, you've been working with Formula 1 drivers, think about the telemetry that they do on the cars now. There's like a constant stream of data that's coming out of that car. They use that data to make sure that the vehicle is performing at the absolute pinnacle of what is possible. Can you imagine letting the car go for a few laps with one of the tire pressures off by just even a few PSI? That would be devastating to the performance of the car.

Tommy:    Yeah, absolutely, and they wouldn't do it unless there was something really stopping them from bringing the car in. Obviously there's a lot of strategy there but, you're right, if you start to see something going off, that will be pounced on and changed immediately. It's very rare that that's happening in just average human health.

    You can go the other way. There are some people who, you look at a test and they read the tea leaves and they have this complex plan of all these things you need to do. We're still a little bit wary of a lot of that stuff but certainly, particularly when it comes to blood markers, particularly when it comes to stuff like that where they've been well-tracked in multiple types of populations, we know we can intervene to change that marker, then just tracking that stuff over time. The fact that the model really picks it up is interesting.

    So we know that the older you get, the likelier you are to die soon. That's just a fact of life. Some of the other things are important in the model. We talked about BUN, we talked about the liver enzymes. We know the metabolic health and risk f cardiovascular diseases, stuff like that, your triglycerides is under 100, it's a really nice marker. You can see that on the model. As soon as your triglycerides go above 100, your predicted age increases rapidly.

    For blood glucose, both or all cause mortality and various things we know that the optimal range is probably between 80 and 90, something like that. Again, in the predicted age model, we told the model nothing about blood glucose, right? It doesn't know anything about -- it doesn't know what blood glucose is, but it knows that as soon as blood glucose is above 90 then predicted age starts to increase and then from 100 to 110 is a big increase. Actually, once it goes above 110, there's not much of a change.

[0:35:05]

    You see that from most of the epidemiological data as well. Some people are like, when they're looking at somebody's blood test, they're like, "Well, the fasting blood glucose is 200 and that's so bad that nothing else matters." Actually, once you're above 110, most of the damage is done and actually it takes much, much bigger increases to see, big increases in biological age as well as mortality and stuff like that. So the fact that we have this idea of ideal reference ranges based on population data and then the predicted age model actually comes up with almost exactly the same ranges from that data.

Christopher:    Right, I'm looking at the chart right here. I can link this in the show notes. There's an explanation of how your serum level of glucose affects your biological age and, yeah, it's what we would call a sigmoid function, so it looks like a stretched out S on its side and something really special happens around 90 milligrams per deciliter. It just takes off at that point. At about 110, like you say, the damage is done, and the model is only going to add five more years onto your predicted age even when it goes up to, cliff the thing at a 150 here. That stays pretty flat all the way up to whatever your fasting blood glucose could ever possibly be. That's really interesting, isn't it, for a machine without bias or even knowledge of what the hell glucose is or even what age is, might learn that from the data I think is important.

Tommy:    Yeah.

Christopher:    Do you think then that abnormal fasting blood glucose in athletes is almost a bad thing? Because this is definitely something we've seen in practice is, what the heck, I'm doing all this exercise and that's supposed to be the thing that disposes the glucose yet I'm waking up first thing in the morning, checking my blood glucose, and it's 105 or something consistently. What the hell is going on there?

Tommy:    I think both the fasting level and the changes, the variability, I think those are both important. If you're 105 and you didn't really deviate that much, that's probably better than being 105 and having a lot of variability, up and down, for various reasons. If your fasting glucose is over 105 or your HbA1c is elevated, and there's a possibility, on the HbA1c side, there's a possibility that if you're really healthy that your red blood cells will level on time and then your HbA1c will be artificially elevated because HbA1c is basically glucose attached to your red blood cells. That's the simplest way to look at it, glycated hemoglobin. That just happens over time.

    So if your red blood cells level on time because they're really robust then that could artificially level your HbA1c. But if your glucose and HbA1c are elevated as an athlete, I think that is something that you should be looking at. There's a lot of information on -- or maybe it's the quality of the diet, maybe it's the inflammatory response to the training that you're doing, maybe it's poor sleep or recovery, maybe it's stress either from the training itself or from all the other things you're trying to do at the same time being a competitive athlete. All of that feeds in and as you start to improve those things one by one, at least people that we work with, we tend to see impressive changes in blood glucose.

    You always hear about that guy who is, oh, he was so healthy. He ran a marathon last week and then he keeled over and died this week. It's one of those things that just because you're an athlete and you look good on the outside, that some of these things are just worth tracking. If they don't look right, it's a good reason to evaluate all the things that you do and all the things you're exposed to. Maybe you're in good shape as an athlete despite of the exercise you're doing rather than because of it, and I think that there's a good number of examples of that.

    

Christopher:    Yeah, it drives me crazy. I still see Google pushing that model of diabetic retinopathy so they trained a convolution of deep neural network which is another machine learning technique that can identify some pathological changes on an image of your retina that occurred due to elevated fasting blood glucose, glucose disregulation, but by the time you're seeing changes in the retina, you're so far down the road, and it just doesn't make any sense to try and find the problem.

Tommy:    I think they're also predicting cardiovascular disease risk from the retina which makes perfect sense because by the time your retina is screwed then your kidneys are screwed, your heart is screwed, all your endothelial lining is shot to pieces and the horse has bolted by -- yeah, and you can get a nice model with a nice prediction but it's probably too late to really intervene that much.

Christopher:    If it was a detector of imminent danger in an airplane, it would go off when the plane is in little pieces all over the floor. It's just too late by then. I just bought this electric chainsaw that I'm having a lot of fun with. It has all these different warning lights that come on. It has got lithium ion battery in it, but it still has bar oil, chain and bar oil. What the hell. I'm figuring out all this stuff this week. You still have to put oil in the thing and it lubricates the chain as it's cutting.

    There are all these fault codes. Something will just stop and just go, beep, beep, beep, and you're supposed to know what these different fault codes mean. The saw just doesn't work until you fix whatever is wrong. It could be the chain tension, or it could be the level of oil in the saw. You have to figure out, and it's just not going to run until you figure that out.

[0:40:00]

    I think the same should be true with some of these markers like fasting blood glucose. If your fasting blood glucose is consistently 105, you need to just stop and figure out why the saw is not running. If you continue, all you're going to do is break the chain or create a worse problem. That's your chainsaw check light. You need to figure that stuff out.

    Well, maybe that's a good place to wrap-up. Are there any other markers you can think of that people should be concerned about, especially the athletes? That's our goal at Nourish Balance Thrive. We're always trying to use data to improve health span and performance, and blood chemistry is one of the best ways that you can do that. We're huge fans of looking inside to see what's going on. Basic blood chemistry is about as good a place to start as you'll find. Is there any other test that you think that people should be using to look inside when they're training or racing?

Tommy:    There's one that we got a question about that we can quickly cover and then -- one is calcium levels and then the other one is cholesterol because we see that elevated fairly frequently. Actually, there's some interesting stuff on the model on that. So the first one is calcium which somebody else questioned about endurance athletes having slightly lower calcium levels, and we did. We have some blood test results. We looked at both athletic and non-athletic populations. The athletic population had a calcium that was like 0.1, it was 9.4 and 9.5, the two, very slightly lower. If you did statistics on it, it probably wouldn't be significantly different.

    There was a paper that showed that acutely after some running, there's a decrease in parathyroid hormone which regulates the amount of calcium that's absorbed in the gut and is regulated by both calcium and vitamin D levels. So the question was, if this is true and this is happening regularly, so if you're running regularly which is decreasing your parathyroid hormone which is decreasing the amount of calcium that you're taking up which then results in lower serum calcium, and that was the question, should we then be adopting the reference ranges for endurance athletes if they have lower calcium levels?

    In terms of our total data set, it certainly doesn't look like that's a regular thing, although it's having a big effect, but I would mention something about the reference ranges which is that, just because -- and I think it goes back to a lot of the stuff we were talking about earlier -- just because a lot of endurance exercise causes your calcium to go down, doesn't mean that I should then change the optimal reference range to reflect that because I'm not necessarily certain that all that endurance exercise is decreasing your calcium. If it is, it's a good thing. It's like the example that Ken Ford gave when he was on a podcast.

Christopher:    I was just going to say [0:42:24] [Indiscernible].

Tommy:    Grip strength, when they tested grip strength in millenials, so it was a year or two ago, versus grip strength in the 1980s, particularly male grip strength, had decreased significantly such that it was about the same as female grip strength. Actually there were some females in millenials who are stronger than their counterparts in the '80s which is great, but the paper suggested, well, we should decrease the normal range for grip strength in males. No, you shouldn't! You should just acknowledge that males are getting weaker, and maybe we should do something about that.

    So, just because some activity changes a marker, doesn't necessarily mean that you should just work around that marker and then say, "Well, we'll change the reference range." If you're somebody who is working with athletes and you see consistently lower calcium, test vitamin D, test parathyroid hormone. If all those look good, don't worry about it, but maybe those are elevated. A lot of athletes do need higher levels of vitamin D, around 40 nanomole or at least, sorry, nanograms per deciliter.

Christopher:    You wrote a whole article on this with Brad Dieter that we linked to in the show notes.

Tommy:    Yeah, so maybe it shouldn't be, let's change the reference range to make people feel better. It should be, let's still use that as a trigger to look inside. If you're measuring anyway, you may as well be testing this other thing. So that's just something that is always worth bearing in mind.

    The other one is cholesterol just because we get a lot of questions about it. There's a paper that just came out, looking at cholesterol levels of keto versus carb-based athletes. The keto athletes had high levels of cholesterol and probably one of the reasons for that goes back to the work of Dave Feldman who we've also had a podcast recently which suggests that those lipoproteins are parts of the energy delivery system and when you are running on your fat stores, largely your own fat as well as dietary fat, then you just need more of those and you get more of those circulating around.

    So we often see high cholesterol, both LDL and HDL and total cholesterol, we see all of those are elevated in athletes because HDL often goes up with exercise and LDL might be going up because somebody is low carb or keto. We do often see that. Is that a bad thing? We're not entirely sure, but if you looked at predicted age, high cholesterol is associated with a higher predicted age.

    This is one of the interesting parts of cholesterol and age and mortality is that as you get older particularly, the higher your cholesterol, the longer you live. So just because something is higher and is predicting a higher age, doesn't necessarily mean that it's a bad thing. It's another one of those things that you need to look at who you are and your circumstances and your environment. Maybe if you're in your 60s and 70s, high cholesterol is a good thing. If you're young and your cholesterol is skyrocketing for some reason, maybe you need to look at your thyroid function or you need to look at your diet or look at some other factors too. All of that is going to come into play.

[0:45:07]

    It will be nice if we just had this simple marker that you just look at it and less is better or more is worse, but there's a lot of stuff that can then hopefully trigger you to better understand your own physiology and then figure out what you need to do for yourself. It's still not the perfect answer, but it gives you a tool to get a better handle on what's going on inside. That's something that not many people have and could maybe take advantage of.

Christopher:    I wish there were more people -- I'm thinking about the traditional coaching model, at least in cycling, where you pay a lot of money for people to look at your power file. You have this power meter on your bicycle and it generates this file, and you pay your coach to look at and give you some meaningful insight from that. You typically pay $500 a month for somebody to do that. I'm thinking, unless you're a wealthy cyclist, how is that ever going to be useful versus running a blood test every -- I'll ask a question, how often would you run a blood test on a competitive athlete, someone who is taking this pretty seriously?

Tommy:    I think every two, three months probably because there's going to be a preseason and an off-season and during the season, something like before the season, during the season or the end of the season, at least once, so middle of the off-season they should be recovering and working on base, whatever it is, aerobic fitness or strength or whatever it is, depending on the sport and associated things. So that would probably -- depending on the length of the season, all that stuff, two to three months is ideal. Very few athletes actually do that, but it could certainly benefit them.

 

Christopher:    Earlier in the podcast, Tommy mentioned a book and he thought it was by Levi Leipheimer. It was of course The Secret Race by Tyler Hamilton. Well, yeah, I hope this has been helpful. If you have any questions, one of the ways that you can try us on, like a sweater, and ask some questions, you don't have to go for the full Elite Performance Program, you can become our patron over at patron@nbt.ai or you can search for Nourish Balance Thrive on Patreon.

    Patrons, they have access to our forum. We have some very nice discourse forum software, and we have a very lively community that consists of both our clients and other patrons and then also a nice collection of coaches. We've got practitioners who are using the blood chemistry calculator. Nearly all of them now are members of the forum so if you want to get in touch with somebody that really understands blood chemistry, that might be a good place.

    On Patreon, so on our other podcast, and it's not some of this podcast, it's an entirely new project where we do more Q&A and more user-driven content, we've just released the first of a series of Ask Me Anything podcast. So if you would like to ask either me or probably Tommy, let's be honest, Tommy, if I'm honest, then you can come over to the forum and you can ask a question there, and we'll be sure to answer that in a future episode of the premium podcast that is being broadcast on Patreon.

    So, thank you very much for your support, we really appreciate you, and see you again soon in a future episode.

[0:48:15]    End of Audio

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