Harnessing the Power of Natural Killer Cell For Enhanced Immunity, Longevity, Performance & Beyond.

Hello, everybody. This is Ben Greenfield. This is kind of a weird podcast today because I didn't expect it to be as good as it actually turned out to be. I got this really smart guy on the show who was going to talk about natural killer cells, which sounds like a really dorky show, but it actually turned into this amazing discussion about enhancing longevity and improving physical performance and a whole lot more. So this Guy's name is Dr. Jonathan Klinthorn, and it's actually, in my humble opinion, a really good episode in this episode of the Ben Greenfield Fitness show.

After a really, really hard workout, right? Like, we've all had that time where, like, I really pushed myself and I got sick two days later. It's after that big workout where you're like, hey, I need to really recover, drive my MTOR expression, and really get my NK cells to be as mature as possible so that they can protect the lungs. Interesting things that people are starting to show is that a lot of the supplements that are beneficial for exercise are also beneficial for NK cel. You don't necessarily need to go out there and buy an NK cell specific thing.

He's an expert in human performance and nutrition, voted America's top personal trainer and one of the globe's most influential people in health and fitness. His show provides you with everything you need to optimize physical and mental performance. He is Ben Greenfield. Power, speed, mobility, balance, whatever it is for you, that's the natural move. Get out there. When you look at all the studies done, studies that have shown the greatest.

Efficacy.

All the information you need in one place right here, right now on the Ben Greenfield Fitness Podcast. Hey, folks. Hey, folks. It's Ben Greenfield. And if you haven't heard of something called an NK cell, then you're about to get your mind blown. You'll see NK cells talked about right now in the field of therapeutics and pharmaceuticals and cancer and even longevity and anti aging. But I've never really talked about them on the show much before. So I hunted down one of the world's leading experts, particularly on the role of nut diet and these NK cells, also known as natural killer cells. So my guest today is Dr. Jonathan Clinthorn. And Jonathan has, like I mentioned, an intimate knowledge regarding the role that diet plays in immune function and this idea that certain nutrients can interact with the function of a type of cell known as a natural killer cell or an NK cell. And he is also an endurance athlete. He got his PhD in Human Nutrition from Michigan State University. He runs, he climbs, he skis in the Mountains of Colorado. And he's co authored a ton of research papers on things like aging and calorie restriction and immune function, inflammation, human nutrition. So he has an expert working knowledge of exactly how to manipulate these things called NK cells on a daily basis to whether you want to want to enhance your immune system or you want to fight cancer, or you even want to perhaps prepare your body and your cells and your immune system for the rigors of intense competition like triathloning or marathoning or anything along those lines. So we are going to have fun today. We're going to geek out. Dr. Clinthorn, welcome to the show, man.

Yeah, thank you for having me.

Yeah, man. And I guess a, a perfect jumping off point here, or jumping on point, as the case may be, would be, what the heck is an NK cell, man?

Yeah, that's a great question. So NK cells are one of the least appreciated but maybe most important parts of our immune system. Natural killer cells were first discovered maybe 40 years ago, take or minus a few years. And what's really interesting about them and kind of where they got their name was that they were co incubated or just kind of put into a test tube with some tumor cells and they found that they would just kill these tumor cells automatically. That's really unique because a lot of our immune cells need some time to adapt and recognize the tumor cell and proliferate so that they can kill it. Whereas NK cells, they don't need that ability, they don't need that time to be able to become cytolytic.

That's what you would call something that could kill a tumor cell. Cytolytic.

Yeah, cytolytic.

Okay, so they found. Now just perhaps a dumb question here, but were these tumor cells in test tubes or are we talking about in what we call in vivo or in human subject, that these things are actually working?

Yeah. So the first observation 40 years ago all came from test tubes. But now we know that natural killer cells provide a crucial part of the in vivo immunity in the body, immunity against anything that's non self. So we're talking about tumor cells, virally infected cells, cells that are on their way to becoming tumor cells. So, you know, early stage of malignancy. They are a pretty big portion of our immune system. When you look at human peripheral blood, natural killer cells are usually between 2 and maybe 20% of total white blood cells. So they do represent this big portion of the immune system. And because they act so fast, they're what we call part of the innate immune system, which is a Part of the immune system that kind of works in the first few days of our defenses. Whereas the adaptive immune system, the other arm of our immune system, usually takes seven to ten days to ramp up.

Right, so the NK cells would be something that would get activated upon acute exposure to some type of immune system. A sal. Exactly.

Yeah. So anytime a cell becomes infected with a virus, the NK cell is the first one there to respond and keep that virus from proliferating too much and spreading so that, you know, the rest of the troops can get some time to mobilize and get called in. I always kind of refer to the NK cells as like the special Forces. You know, they. They go in first, they try to keep things under control until you can get the rest of the army called in.

Okay, that makes sense. Now, I took some pretty advanced human nutrition courses when I was attending University of Idaho. I got a master's degree in exercise physiology and in biomechanics. But I studied a lot in nutrition. And we talked about carbs, and we talked about proteins, and we talked about fats and micronutrients. We did not talk about NK cells that extensively. And so I'm curious for you, getting a PhD in human nutrition, how'd you actually get interested in this topic of natural killer cells in the first place? Because you don't exactly see them when you. When you pop open the average nutrition book.

No, in fact, you might not see them at all. From an immunology standpoint, they're recognized by most immunologists, but from a nutritional standpoint, unfortunately, they're not really talked about much. I became interested in them. I was doing my PhD on something called caloric restriction, and we were studying how caloric restriction could improve lifespan. If you're familiar with caloric restriction, you restrict calories anywhere, 20 to 40%. So for the human equivalent, 1200, 1500 calories a day, you get to live to 120.

But the problem is that you don't actually get to eat a donut.

Yeah, no donuts, no sex life. You're cold all the time.

Cold, hungry, but long lived. Yeah.

So you prolong the misery. So with caloric restriction, one of the things that happened before I started in this lab was that they noticed that it was great until calorically restricted animals were challenged with an infectious pathogen. So whether it be a gastrointestinal virus or bacteria, or specifically in my lab, we were looking at how calorically restricted mice were more susceptible to influenza virus infection. And so, you know, I kind of had to blend the fields of immunology and nutrition to understand how a nutritional intervention like calorie restriction might alter the immune system and see its impacts on an immune cell. So I spent five years really trying to figure out, hey, what was this immune cell that's not working very well? What's its role in influenza infection? And then why isn't it working in these calorically restricted mice? Is there anything we can do to circumvent this problem?

So you found that in a state of caloric restriction, NK cells actually appear to. To be subjected to some kind of a deleterious effect.

Yeah, it was a very complicated process because natural killer cells, they're not uniform. There are all these different subsets of this really important cell type. And some things that caloric restriction was doing really improved the function of natural killer cells. So if you just look at their peripheral function, if you take it out from the blood, for example, you see that the natural killer cells in calorically restricted mice, and part of that was because they're actually stuck at a stage of their maturation where they don't fully develop into the full cytolytic cell, but they have a very low inhibition threshold, which I can talk a little bit more about later. Unfortunately, only these fully mature cells will populate the lungs. So when we were looking at this respiratory virus, and we were seeing that it was very lethal in calorically restricted mice, we eventually found out that because caloric restriction wasn't allowing nk cells to fully mature, they weren't able to populate the lungs very well and weren't able to provide very good defense in the respiratory system.

Okay, gotcha. Now, you mentioned to me when we were talking about nk cells and what you knew about them and what you wanted to mention on them, one thing that you talked about was this idea of maturation and homing. And homing isn't really a term I'm not familiar with when it comes to cells. I know a little bit about maturation of a cell. But why. Why is maturation and homing important when it comes to nk cells? Why is that something that we would need to talk about?

Yeah, I mean, just like. Just like humans, we all have to grow up, right? So natural killer cells begin their lives in the bone marrow, where they slowly develop a functional competency. They learn how to work, they learn how to function. And really, interestingly, in the bone marrow, natural killer cel licensing. And what this means is that certain natural killer cells are actually given what we call a license to kill. And that license to kill means that these cells have matured to a point where they can then kill any. Any cells that they might have.

Literally. That's why they call them licensing.

Yeah.

Interesting.

And so licensing all happens because not all natural killer cells will develop what we call an inhibitory receptor that's specific to our self. So inhibitory receptors are kind of these probes that natural killer cells use to probe the other cells that are around in the periphery and, you know, see what's going on with them. And when you have an inhibitory receptor specific to self, it recognizes your cells as, hey, these belong to me. These are part of my body. I don't want to attack them. And so really, you know, amazingly, our bodies have given our NK cells an ability to become licensed once they do have that ability to recognize self. And that keeps NK cells then from being able to kill self cells and reduces their incidence of involvement in autoimmune diseases.

Okay, so when an NK cell matures, it actually becomes licensed, it has this license to kill, and at that point, it's able to act against these acute immune system assailants that you're talking about.

Exactly.

Okay, an acute immune system assailant, by the way, would that be something like a peanut exposure or a bee sting? Or are we talking about more like exposure to cancer, influenza, things along those lines?

In the case of a natural killer cell, we're definitely talking about a transformed cell. So that would be a cell that's become infected by influenza virus or that's transformed into a cancer cell.

Okay, gotcha. So how does the NK cell actually work when it comes to identifying self versus non self? Meaning, you know, how does it actually learn to fight off something like influenza or something like cancer versus fighting off the body's own tissues in what we would call an autoimmune type of reaction?

Yeah, so that's a great question. So what NK cells actually have are a set of activating receptors and a set of inhibitory receptors. And anytime that they encounter a cell, they kind of probe that cell with both activating and inhibitory receptors. And whichever set of receptors gets a stronger signal will determine how the NK cell responds. So if you've encountered just a normal, you know, heart cell, lung cell, you're going to get a really strong inhibitory signal, and the NK cell won't become activated to kill that cell. But in the case of a virally infected cell or a tumor cell, the activation signal is gonna be so much stronger because of oncolytic proteins that are being expressed on that cell's surface. It's gonna actually activate the NK cell. It's gonna overwhelm that inhibitory threshold. And now these lysin NK cells can go ahead and kill whatever they've encountered.

Got it. So in the bone marrow, the NK cell matures, it's given the license to kill. It recognizes the proteins on the surface of something like a carcinogenic cell, and at that point it can kill that cell.

Yeah, and you know, they are going to leave the bone marrow egress throughout the periphery. We'll have them in our blood. There's a fairly large population of them in the lung as well. So about 25% of resident immune cells in the lung are NK cells, as well as pretty large population in the liver.

Okay, gotcha. Now, one of the things that flies around at this point in the realm of talk of, let's say, fighting cancer, is this idea that cancer is a metabolic disease, that it's a failure of the mitochondria to function properly, and the generation of huge amounts of lactic acid, for example, and the consumption of glucose by a cancer cell. Is there any relation between NK cells and this idea of the metabolic theory of written about in books like Tripping over the truth is one. Dr. Mercola recently came on the show and talked about this in his book Fat as Fuel. Is there any link between those theories and NK cells that you're aware of?

Yeah, it's really interesting when you actually look at immune cell metabolism. Most people for a long time just figured immune cells had the same metabolism as every other cell. But immune cell metabolism is becoming increasingly more important for understanding how immune cells become activated and work. So a lot of immune cells actually use what's called Warburg metabolism, and that's kind of the same metabolism that cancer cells use. So it's kind of their way to work in the same environment that a cancer cell might be working in. So Warburg metabolism. When a cancer cell is using Warburg metabolism, it's able to create a lot of energy in a very hypoxic situation where there's not a lot of oxygen available, which can suppress a lot of immune function, suppress the ability of immune cells to work in that area. But when you have another immune cell that can use Warburg metabolism, it's able to work in those low oxygen conditions and actually become activated and work during that time.

Okay, so in other words, an NK cell can actually operate on glucose inside of an area where there's cancer by using this Warburg style of metabolism to allow it to actually fight a cancer cell but survive in the metabolic state that a tumor would be in, for example.

Yeah. And actually when it does receive those activation signals, it switches it over into that Warburg metabolism so that it is able to work during those times.

Interesting. Okay, so in other words. Well, this begs the question, I suppose if someone were shifting to a ketogenic diet, for example, to control something like cancer, to shut off blood glucose, you know, from a cancer cell, wouldn't you theoretically be shutting down the ability of an NK cell to function?

You know, that's definitely a concern. One of the unique things about NK cells is that unlike a T cell, they don't need to proliferate and expand to respond. And that's kind of what the metabolism used by T cells is really important for. So NK cells, you know, they can just degranulate, which is how they kill cells. They release something called granzymes or perforins that poke holes in their target cells, and then they can die if they don't have enough energy available, but they still are able to at least exert their functions.

Okay, gotcha. That makes sense. Makes sense. Okay, so we, we obviously have, have pulled back the curtains to a certain extent in terms of what an NK cell is, but what I love to delve into is the practical nitty gritty when it comes to how to actually apply some of these concepts to real life. Or in this case, for you as a doctor of human nutrition, apply this stuff to dietary factors. Are there dietary factors, things that we can do in our diet that would either help or hinder NK cell function?

Well, one of the things that really drew me to NK cells was that they are extremely sensitive to dietary factors, especially when you look at the metabolism and the effects of different metabolic products on NK cells. So you're probably definitely familiar with leptin, for example. So leptin is really important for the function of NK cells. And leptin is this hormone that's produced by fat cells. And if you don't have enough leptin, you won't have NK cells being produced. They won't be maturing, they won't be surviving. So it's really interesting to look at how dietary factors play in especially energy metabolism. And that's kind of where my studies led me, was looking at how different energy sensing pathways within NK cells were responsible for the maturation and the function of NK cells, which then kind of controlled their ability to home to different tissues.

And what have you found thus far in terms of dietary factors in NK cells?

Well, if you look at the total body of literature, there's a lot of different factors that can play a role. Like I said, leptin can. Caloric restriction, working through what's known as the mammalian target of rapamycin or mtor, has a big role in the maturation and development of NK cells. And then there's also some little bit simpler ways to just kind of boost NK cell function without really messing with their development. And those include things like some of the glucans that, you know, these undigestible starches that are actually immunostimulatory. One that comes to mind that my lab did a little work with was active hexose correlated compound, which is a mushroom extract from shiitake mushrooms. Yeah, there's some other glucans that come from other types of mushrooms that have been studied for boosting NK cell function.

Are there certain types of mushrooms? Because on this show I've actually interviewed a couple of folks who do things like dual extracts of chaga and rishi or who, who grow mushrooms on a mycelium medium for everything from medicinal purposes to enhancing cognition to enhancing the immune system. Are there certain types of these, you call them active hexose correlated compounds from mushroom extract that are particularly effective at enhancing the function of our NK cells?

Yeah, it seems that the ones from shiitake mushrooms are especially important and those are providing alpha glucans. And, and then there's also some evidence that beta glucans can do this too, and those are found in a few other types of mushrooms.

So shiitake would be one good example.

Yeah.

Okay, so as far as something else that you mentioned in addition to mushroom extracts, I believe that you said that this idea behind MTOR and calorie restriction appears to be favorable or unfavorable for these NK cells.

You know, it's really specific to, you know, the situation that you're in. So at a general level, calorie restriction seems to be pretty good for NK cell function. It seems to kind of trap them in a maturational stage where they're not fully mature, but just mature enough that they can kill pretty easily. The biggest problem is that they don't mature enough to be able to get to the lungs. So calorie restriction is going to be really good if you're just looking for, you know, your day to day NK cell tumor surveillance so that you just want to have really good NK cells that can float around throughout your bloodstream and, you know, look for tumor cells and kill those. Calorie restriction or intermittent fasting, which both can inhibit MTOR are both going to be pretty good for NK cells. But, and you know, this is the contextually specific part, if you are at an increased risk of developing a respiratory infection, you really need to actually kind of push your NK cells into a more mature phenotype and try to get them to home to the lungs, because only these mature cells can get to the lungs to try to really provide respiratory defense. And I think that's where it kind of comes in handy for athletes, because athletes are at such a great risk of developing respiratory infections either, you know, when they're training really hard or after really big events.

And so for athletes, and this is actually, this is actually a very relevant and important point, I think, you know, there's a lot of literature that shows that when someone's training for an event, right? Like when I'm training for a Spartan or you know, back in the day when I was doing Ironman, or I know that you're an ultra endurance athlete competing in all sorts of events. Upper respiratory tract infections are a huge issue, like just getting knocked out for a few days, being unable to train, or feeling like crap when you do train, or needing to stay aerobic because you can't really suck much oxygen into your lungs. It's an issue. Now, when you say that activating NK cells can help with, with either recovering from or protecting you from these respiratory infections, are you saying that intermittent fasting and caloric restriction would or, or would not be a good idea in this case?

You know, what I like to tell people is that you want to eat a smart, healthy diet that's going to more or less not over activate your NK cells. So this would be a diet that is going to be maybe intermittent fasting, using some ketogenic diet principles as a daily basis kind of diet. And then when you really need to, you're ramping up your training or you're getting ready for a big event or right after a big event, that's the time to really try to push your NK cells into this more mature phenotype. So it really comes down to, you know, those times after a really, really hard workout, right? Like we've all had that time where you're like, I really pushed myself and I got sick two days later. It's after that, that big workout where you're like, hey, I need to really recover, drive my, my mtor expression and really get my NK cells to be as mature as possible so that they can protect the lungs.

And maturation would occur with actual feeding or with fasting.

The maturation will occur with feeding. So it was really interesting how energy responsive the NK cells are. In our studies we just did simple refeeding experiments where we allowed our little calorically restricted mice to gorge themselves and it would immediately boost their NK cell numbers. Immediately boost their NK cell numbers of mature NK cells as well. So they are really, really hyper responsive to these fluctuations in energy balance.

Okay, interesting. So a strategy then for an athlete who wanted to optimize well, body composition and immune function, perhaps their metabolic fat burning efficiency, but also their ability to be able to bounce back from very difficult workouts or competitions without getting ill, would be to engage in intermittent fasting or caloric restriction, which also of course has a little bit of an anti aging and longevity effect. But then have periods of time, specifically in intense post workout scenarios where you would eat ad libitum or you'd eat a higher number of calories or a higher number of carbohydrates than you would under normal circumstances. And that would enhance your NK cell function or your NK cell maturation, I suppose.

Yeah, no, that's exactly it. And what's really interesting is that this kind of regulator of NK cell maturation, mtor, it also regulates muscle anabolic processes. So driving MTOR after a really hard workout is not only going to help with your immune system, but it's also going to help with your, you know, muscle recovery as well. And some of the biggest MTOR drivers out there are our branch chain amino acids. So you know, making sure you get that, that whey protein after your workout can really help drive MTOR to recover your muscles and help boost your immune function.

Interesting. Okay, cool. This is fascinating. So we've got things like shiitake mushrooms for the active hexose correlated compounds or these glycans. We've got periods of fasting and periods of feeding depending on the circumstance. What are some other nutritional factors that can affect NK cells?

Well, there's actually been some interesting studies looking at resveratrol, which is the active compound in red wine, as a booster of NK cell function. And it's been specifically looked at with exercise physiology too. So you're kind of getting that interplay again of exercise phase and immunology where resveratrol can boost NK cell function. Other beneficial things for NK cell function.

Now just backing up there for a second with wine, of course you often hear the complaints that the studies done on resveratrol involve one needing to drink like, you know, hundreds of bottles of wine to achieve that effect. Are you talking literally about a nightly Glass of wine. Are you talking about actual resveratrol supplementation using some type of a pill or a capsule or a powder or something like that?

Yeah, I think you're going to want to go with the pill or capsules or powders. The studies that are looking at this are using, you know, 1 milligram per kilogram resveratrol, which in human equivalence is quite a bit of wine. So I think you'd really prefer using the supplements.

Okay, so when you're using something like resveratrol, obviously that has a little bit of an antioxidant or an anti inflammatory effect. Would you be concerned at all about that, that blunting the hormetic response to exercise if you were to take that on a regular basis, for example, at that dosage?

Yeah, absolutely I would. And I always recommend to people with antioxidant supplements to kind of leave them out of their training regimen and just use those for recovery from your big race so that you don't get sick after your race as opposed to using an antioxidant supplement throughout. Because you really do need that hormetic response.

Yeah, yeah. Well that's, that's certainly something that, that I've, I, I've adopted the habit of, is only in, in a post race scenario or when I'm traveling across many time zones, you know, and exposed to a lot of, you know, jet lag and airline radiation and toxins and pollutants and things along those lines. That's when I'll do things like Myers cocktail IVs or higher doses of eritrol or liposomal vitamin C or glutathione or a lot of these things that can actually blunt the body's ability to produce its own endogenous antioxidants. But those are situations where the pros outweigh the cons. But you're saying that just because you've purchased a resveratrol supplement doesn't mean you need to be using on a daily basis and it may in fact be be not such a good idea when it comes to exercise adaptations.

Yeah, there's quite a bit of literature looking at how over supplementation with antioxidants can blunt the adaptation to exercise due to the lack of hormetic responses.

Gotcha. Could the same be said for something like curcumin?

Yeah, well, you know, that was another one that we had kind of talked about as far as being an NK cell modulator. One of the unique things about curcumin is that not only does it work as an antioxidant, but it also seems to be involved in some redox signaling and activating what's called NRF2. Are you familiar with NRF2?

A little bit, but go ahead and fill our audience in on it.

So NRF2 is the master regulator of a lot of our endogenous antioxidants, our body's own antioxidant responses. So NRF2, when it becomes activated by free radicals or curcumin, will then go down to the DNA and, you know, regulate the transcription of glutathione and these other important antioxidant defenses that our body knows how to make naturally. So curcumin is really interesting because it does work as an antioxidant, but it also seems to kind of work on the back end by supporting our normal hormetic responses.

Okay, gotcha. So curcumin would be one strategy here, and again, being careful, careful when that's actually used, and saving it for the more difficult scenarios when you really want to activate NK cell function and enhance your immune system. Resveratrol would be one shiitake mushroom extract. You talked about that a little bit. What else is out there that has an effect on NK cells?

You know, one of the hottest fields right now you have to always give credit to is probiotics and prebiotics. Those things are so hot. Understanding how probiotics work is probably the future of all nutritional science at this point. You know, all the nutrients, they have to go through the gut before they make their way to the body. So how are those bacteria in our gut interacting with those nutrients? And then what are those bacteria producing that's influencing our immune function? So about 70, 80% of our immune system is actually located in the gut. A lot of interaction between bacteria and the immune system goes on there, and it can help train, program our immune cells. Those immune cells aren't then trapped in the gut, but they can travel throughout the body where they exert some of their phenotypic effects, especially when we're talking about something like the lungs, which is another mucosal tissue. And a lot of people will say that the mucosal tissues are all kind of functionally linked, whereas the lungs and the gut can kind of talk to each other, and immune cells can traffic between the two of them pretty easily because there are these diverse communication networks. So definitely probiotics is something to consider. There are specific strains with probiotics. You always want to look for a strain that's going to be researched for what effect you're looking for as opposed to just doing general probiotics. But some of those probiotics that are good for NK cells are a lot of the Lactobacillus, Lactobacillus gasseri, Lactobacillus casei, Lactobacillus para caseae are both really important for NK cell function.

So what you're saying is that bacteria in the lungs can take cues from bacteria in the gut.

Actually, the immune cells in the gut that take cues from the bacteria in the gut travel to the lungs and provide protection in the lungs.

Okay, so by using a probiotic, you actually can affect respiratory function.

Yes, absolutely.

Interesting. That's not something I thought too much about before, but. And you're saying some of these more popular strains like Lactobacillus or Bifidobacterium would be appropriate for a scenario like that. You don't to have to use some kind of a fringe probiotic?

I don't think so. I think a lot of the research has focused on some of the more basic ones and they've seen good effects with NK cell function. You know, if you Google probiotics and NK cell function, you'll see a bunch of studies pop up that look at a probiotic and seeing how it increases the ability of NK cells to kill when they just take blood from humans that are just, you know, taking a probiotic.

Got it. Interesting. Okay, well, cool. That's. That's good to know. I use one called Probiotics Advanced right now, and it has, I think about six or seven of the different Lactobacillus strains in it, and then something called Gonadin bc and I think there's a streptococcus in there as well. So I think I've got my bases covered from the probiotic standpoint. What about amino acids? You had mentioned to me that there's this concept of MTOR agonists or amino acids. Can you go into what an MTOR agonist actually is and why that would or would not be useful for something like respiratory tract infections or the activation of NK cells?

Yeah. So, you know, every cell in our body is going to have an MTOR protein being expressed. And when you consume the right amino acids, specifically leucine, which is one of the branch chain amino acids, it will bind to MTOR and actually increase the activity of MTOR within that cell. Once MTOR has been activated in that cell, you see all the downstream effects like gene expression in NK cell specific context, we're looking at maturation, we're looking at increase in Cytolytic function. So these cells are now able to be activated. So really, you know, making sure you're getting your branched chain amino acids post workout, post really hard race, even during races, is really important for increasing MTOR activity. And I always tell people branched chain amino acids are pretty prevalent in the diet, but if you really want to get them looking at whey proteins and some other really high branched chain amino acid protein supplements are a great way to go.

So very similar toto overfeeding. This is not something you'd want to necessarily do constantly if you were coming at this from a longevity and an anti aging standpoint, because you wouldn't want high levels of leucine all the time, because that would be considered an MTOR agonist. Right. If you were in a scenario where you needed to help your immune system as much as possible, assist recovery as much as possible, ditching the idea that you want to be cold and hungry to be able to live a long time, then you'd want to increase the availability of leucine. And this is where you could use a scenario like a branched chain amino acid, or in my case, I actually use a whole amino acid, an essential amino acid complex. But anything that would have something like leucine in it would actually be able to agonize or activate MTOR and increase the activity or the maturation of these NK cells. Yeah.

In some unpublished research in my lab, we actually incubated immature NK cells with some leucine and saw that it activated MTOR in them and drove their maturation processes.

Interesting. Cool. Okay, so is there anything else that from a, from a dietary standpoint, you would, you would recommend. And I have a few other questions I want to ask you after that. But while we're on the subject of diet, anything else that would have an effect on NK cells?

You know, we've been talking about things to take to boost NK cell function, but there's also a couple things that we should probably avoid. One of the biggest is unmetabolized folic acid, or just folic acid in general. Folic acid is the synthetic version of folate, vitamin B9.

This is what you would find in like a, like a cheap multivitamin, for example.

Yeah, exactly. And folic acid being this synthetic version, it doesn't get converted into the active biological form very well. I'm sure you're familiar with the people who have MTHFR mutations where they can't convert folic acid into 5 methyltetrahydrofolate very well. And it's not just those people who seem to be at risk with taking folic acid, but just about everybody, if you look at population based studies, has this unmetabolized folic acid circulating in their bloodstream. And one of the big problems with unmetabolized circulating folic acid is that when you look at the cytolytic potential of NK cells and then measure it in a gradient against the amount of unmetabolized folic acid in someone's circulation, they're negatively correlated. So that the more folic acid you have, the less your NK cells are functioning. And that was just an observational study. Maybe that was made 10 years ago, but since then there's been some really nice animal work done out of Tufts University where they actually showed that giving mice high doses of folic acid suppressed NK cell function directly. And they could look at the NK cells and show that they weren't able to kill tumor cells as well.

And it's very interesting. This is something I've talked about for a while is this idea that if you look at a multivitamin, turn over the label. There's two things I look for to see if it's a good multivitamin. Number one, does it have high amounts of vitamin D in it, unopposed, by or not accompanied by vitamin K and preferably vitamin A as well? Like, is it just kind of like a whole bunch of vitamin D, which a lot of multivitamin companies are doing now? Because vitamin D is kind of like the darling of the supplement industry, but it has some toxicity with regards to calcification when you take a whole bunch of it without things like vitamin K or vitamin A. And then the other thing I tell people to look for is the form of folate actual, as you referred to, methyltetrahydrofolate, or is it this folic acid? And if it's the latter, if it's the folic acid, then you should probably just put it back on the shelf or stray away from the clicking add to cart button on the Internet, because it's probably not that great.

Yeah, folic acid is one of those things that is kind of flying under the radar, but it could be a very problematic thing for a lot of people because a lot of people don't know or their bodies aren't quite capable of metabolizing it.

Okay, gotcha. So avoid synthetic multivitamins that contain folic acid. Basically.

Yeah. Or your B complex. You know, take a look at your B complex, because a lot of B complexes also have folic acid in them.

Okay. Interesting. And would that show on the label of a supplement if the B complex or the B vitamins in there actually had folic acid in the form that isn't methyltetrahydrofolate?

You know, that's a great question. A lot of labels say folic acid, some just say folate, which you need to be careful. I always recommend contacting the manufacturer if it does say folate to ask them what form it is. But because this issue with folic acid is becoming more recognized, we're seeing a lot more methylfolate supplements going on the market. So you'll see these methyl B vitamin supplements that contain methylfolate as well as methylcobalamin, which is the methylated form of vitamin B12.

Gotcha. Okay, Soso we've got resveratrol and curcumin probiotics, avoiding folic acid, ensuring that we get some kind of a glycan from a good mushroom extract. Be smart about when we fast and when we feast. So these would all be strategies that would assist with not only recovery from exercise or avoiding respiratory tract infections from hard training, but I would imagine just generally good things for the immune system in general, correct?

Yeah, absolutely.

Okay, gotcha. Now, what else from like a real life concept, whether nutritional or otherwise, can we do to do things like enhance the immune system or to utilize some of these concepts that you've studied?

Yeah, you know, it's just, it's all about nutrient timing. I think that you could have conversations forever about when nutrients should be consumed and it goes the same for when energy should be consumed. You know, timing your energy intakes to be in accordance with your energy expenditure is so important. It helps your metabolism balance itself out. And your immune system, which is relatively quiescent, it doesn't use a lot of energy when you're not sick, needs a lot of energy when it's time to respond. So making sure that you feed your immune system is just so crucial.

Now where do you draw the line with this? Because for example, when I interviewed Mark Sisson a few months ago, we talked about how fasting post workout can actually be favorable for growth hormone and for testosterone. So do you personally fast for a while after you've worked out and, and then feed and let's just say it's a typical workout. Right. I think we've established the fact that after a very difficult, soul crushing race or workout, you probably should go out of your way to take care of your immune system, to feed and to use some of these nutrients that we've talked about. What about just like on an average day to day basis, do you actually kind of keep your body from getting fuel into it just to allow it to get some of these enhanced growth hormone or testosterone responses?

Yeah, no, I agree with what Mark's saying. I think that it's really, you know, when we're just kind of moving around, when we're just kind of getting our workout in for the day, that's when it's time to really take advantage of what intermittent fasting can do. And at the same time, intermittent fasting is also going to boost some of the effects of the NK cells so that they're providing general tumor surveillance better. They might not be able to get to the lungs, but they're going to be floating throughout the rest of your body being very, very effective. There are actually studies showing that intermittent fasting can boost one aspect of NK cell function called trail mediated killing, where they bind to a tumor cell and then kill that tumor cell by essentially just telling it to die. And so intermittent fasting can be really good. If you're looking for that general immune surveillance. It's when you about being sick that you might want to take advantage of some of these concepts.

Got it. Okay, cool. Now for you personally, what would a typical kind of on a harder training day, let's say you were to take for a lot of endurance athletes, for example, which I know you are, let's say like a weekend, what would your as a PhD of nutrition, what would your typical day of eating look like in conjunction with the workout?

Yeah, so I like to run really far, really long in the mountains, really high. And for me, I like to start my runs fasted so I won't eat anything, you know, wake up in the morning, get out the door and we'll usually run for four, six, eight hours. And during, yeah, during those times I take in a little bit of calories, just enough to keep me from fully bonking out. And then as I work my way back down, depending on how I'm feeling, I'll either really feast or I'll just chill out for a while, drink some water, kind of see how long I was out there. But usually after those big, big efforts, that's time to really gorge yourself and get your body ready to go again. If I'm just going out for 45 minutes, an hour, hour and a half, that's when I'm not going to be trying to drive mtor. I don't really want to over activate my cellular responses off those little responses. I want my body to be Ready to respond off the biggest, you know, eight hour days.

Got it. And what are you eating during your very long runs like that?

I have to admit that it's just about anything I can find.

Right.

A lot of times it's gonna be just snacking on trail mix. Sometimes it's a couple goos, sometimes I'll just reach for a Snickers bar. I am kind of the opinion that when you're working really hard, when the furnace is burning really hot, it doesn't really matter what kind of fuel you put in it. It's kind of what you do before and after that it's really important to think about food quality.

Well, you're certainly not having to worry too much about a big release of insulin when you're out there training. But that's something I've talked about before to folks. I'll recommend things like exogenous ketones and amino acids and a good digestible carbohydrate like a potato, dextrin based carbohydrate and then some electrolytes, you know, mixed into a water bottle or a flask for the very long workouts. But then, you know, and I would do this during Ironman, I'd occasionally just swing by the, by the gas station and grab an ice cold Coke, you know, 80 miles into a ride just because. Just because it fricking tastes good and keeps you going. So yeah, there's certainly those scenarios where there's just a matter of putting fuel into the gas tank. Same thing with Ironman triathlon. Right. Like I'd. The way I coach my athletes is they'll consume relatively reliable and clean burning fuel sources up until the point where I tell them they really need to pull the chute in the race. And that's about the half iron man or the half marathon mark of the Ironman where all the way up to that point it's dietary management, it's staying relatively aerobic. And then 13 miles in you start to go hard and at that point I tell them there's one thing that you should eat and that's coke. The, the liquid coke on ice at each aid station that you run by. Because at that point it's like crack cocaine, literally. But up until that point you, you manage your diet. So yeah, it's an interesting concept.

Time to put the fuel on the fire at that point. Right?

Exactly, exactly. So is there anything else that you want to share with folks when it comes toto NK cells? Anything else you've discovered? Anything you haven't had a chance to Harp on yet so far in our interview.

Interesting things that people are starting to show is that a lot of the supplements that are beneficial for exercise are also beneficial for NK cells. So you don't necessarily need to go out there and buy an NK cell specific thing. You can really like, look at some of the things that you might already be taking on your exercise regimen. Things like fish oil, things like phospholipids like phosphatidic acid or phosphatidylserine branch chain amino acids. All these things can actually help boost NK cell function. So by using some of these typical supplements you might actually be benefiting both your immune system and your recovery from exercise. And I think that's really crucial because you don't have to go out there and spend a ton of extra money. This is something that you know, as long as you're making sure to do on a regular basis, you're making sure to emphasize after big hard efforts you really will be seeing dual benefits.

Yeah, and these are all practical things that I mean obviously it's not that difficult to find. You know, the kind of the stack we've talked about would be some type of shiitake mushroom extract. And by the way, for those of you listening in, I'm going to put a list in the show notes for the things that you could have on hand in your kit, so to speak, for the post hard workouts or the post races. BenGreenfieldFitness.com Go to BenGreenfieldFitness.com killer cells and I'll have all this there. But basically we're talking about some type of like a shiitake mushroom, some type of resveratrol, the one that I have and also the multivitamin I used by Thorne, the resveratrol is called Resvera cell and then I think it's just their Thorn multivitamin elite is the one that has the methyltetrahydrofolate in it, curcumin. And speaking of Thorn, they have one called Meriva which is a lot of curcumin is notoriously poorly absorbed but in a phytosomal format. A lot of companies will use this. I think it's from Italy, Meriva, it's a form of curcumin that's in a phytosome format so it's more easily absorbed. Probiotic with a lactobacillus strain and then some type of amino acid that has leucine in it. That would be kind of the stack for this.

Yeah, that sounds like a good stack to me.

Cool. All right. Well, I'll add this to the show notes and if you have questions or comments for Jonathan or for me, you can leave them right there in the notes. Again, it's@BenGreenfieldFitness.com killersells One last question for you, Jonathan. Are you off to do any epic race or epic events coming up in terms of how are you going to take these four to six hour runs and bring them into the streets?

I'm planning on doing a circumnavigation national park soon once the snow's all melted out there. I'm looking forward to that. And I got a couple hundred milers in the fall, so it's time to get busy.

And you said a circumnavigation of what? You broke up for just a second.

It's a circumnavigation of Grand Teton National Park.

Oh, interesting. How long will that be?

Somewhere in the neighborhood of 35 to 45 miles, depending on how lost I get.

Cool. That sounds amazing. Well, have a blast with that, man. And thanks for coming on the show and sharing all this stuff with us.

Yeah, thank you so much for having me.

All right, folks. Well, I'm Ben Greenfield along with Dr. Jonathan Clinthorn signing out from BenGreenfieldFitness.com head over to BenGreenfieldFitness.com killer cells for all the show notes and to leave your questions and comments. And thanks for listening in. You've been listening to the Ben Greenfield Fitness podcast. Go to BenGreenfieldFitness.com for even more cutting edge fitness and performance advice.