July 1, 2017
[00:00] Introduction/Earth Runners
[01:48] Kimera Koffee
[04:18] About Dr. Jonathan Clinthorne
[06:13] What Is an NK Cells
[09:30] How Jonathan Discovered the Link Between NK Cells and Calorie Restriction
[12:50] Why is Maturation and Homing Important in NK Cells
[15:20] What Keeps NK Cells From Destroying Your Own Tissue
[17:10] Link Between NK Cells and Metabolic Theory of Cancer
[20:37] Dietary Factors That Help or Hinder NK Cell Function
[22:52] The Active Hexose Correlated Compound Particularly Effective for NK Cell Activation
[28:58] Some Other Nutritional Factors That Can Affect NK Cells
[35:51] Commercial Break/Organifi Green Juice
[37:09] Health IQ
[38:05] What an mTOR Agonist Is
[40:50] Why You Should Avoid Folic Acid and Folate on the Label of a Multivitamin
[45:16] What Are Other Things To Do To Enhance The Immune System
[47:47] Typical Day of Eating and Workout of Dr. Clinthorne
[55:57.7] End of Podcast
Ben: 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 to be. I got this really smart guy in the show who is gonna talk about natural killer cells which sounds like a really dorky show, but it actually turn into this amazing discussion about enhancing longevity, and improving physical performance, and a whole lot more. So, this guy’s name is Dr. Jonathan Clinthorne and it’s actually in my humble opinion, a really good episode.
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In this episode of the Ben Greenfield Fitness Show:
“After a really really hard workout, we’ve all had that time we’re like I really pushed myself and I got sick 2 days later. So after that big workout, we’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 cells. So you don’t necessarily need to go out there and buy an NK cells specific thing.”
Ben: 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 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 nutrients and diet and these NK cells, also known as Natural Killer Cells. So, my guest today is Dr. Jonathan Clinthorne and Jonathan has like I mentioned an intimate knowledge of 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 know as 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 expect working knowledge of exactly how to manipulate these things called NK cells on a daily basis to whether you want to enhance your immune system, or you wanna 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, marathoning, or anything along those lines. So, we are going to have fun today. We’re gonna geek out. Dr. Clinthorne, welcome to the show, man.
Dr. Clinthorne: Yeah. Thank you for having me.
Ben: Yeah, man. And I guess say, a perfect jumping on point as the case maybe would be, what the heck is an NK cell, man?
Dr. Clinthorne: Yeah. That’s 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 kinda where they got their name was that they were co-incubated or they’re just kinda put into a test tube with some tumor cells and they found that they were just killed these tumor cells automatically. That’s really unique because a lot of our organ cell needs some time to adapt and recognize the tumor cell and proliferate so that they can kill it. Whereas, NK cells don’t need that ability, don’t need that time to be able to become cyctolytic.
Ben: That’s what you would call something that could kill a tumor cell. Cytolytic.
Dr. Clinthorne: Yeah. Cytolytic.
Ben: Okay. So they found now just, perhaps a dumb question here. But were these tumor cells in test tubes or are we talking about what we call in vivo or in human subject that these things were actually working?
Dr. Clinthorne: Yes. So you know, 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 early stage of malignancy. They are 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 kinda works in the first few days of our defenses whereas, the adapted immune system, the other arm of our immune usually takes 7 to 10 days to ramp up.
Ben: Right. So the NK cells would be something that would get activated upon acute exposure to some type of immune system assailant.
Dr. Clinthorne: 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 the rest of the troops can get some time to mobilize and get called in. I was kinda refer to the NK cells as like the Special Forces. They go in first, they try to keep things under control and so you can get the rest of the army called in.
Ben: Okay. That make sense. Now, when I took some pretty advance human nutrition courses when I was attending the 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, 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 ‘cause you don’t exactly see ‘em when you pop up open the average nutrition book.
Dr. Clinthorne: No. In fact you might not see ‘em at all. From an immunology standpoint, they’re recognized by most immunologist but from a nutritional standpoint, unfortunately they’re not really talked about much. I became interested in ‘em when 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 20-40%. So for the human equivalent it is 1200, 1500 calories a day.
Ben: Right. You got to live to 120 but the problem is that you don’t actually get to eat a donut.
Dr. Clinthorne: Yeah. No donuts, no sex life. You’re cold all the time.
Ben: Cold, hungry but long lived.
Dr. Clinthorne: So yeah, you prolong the misery. So with caloric restriction, one of the things that happened before I started in this lab was that they notice that it was great until calorically restricted animals were challenged with an infectious pathogen. So whether it’d 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 I kinda 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 impact on immune cells, so I spent 5 years really trying to figure out, hey, what was this immune cell that’s nit working very well. What’s its role in influenza infection and then why it isn’t working in this calorically restricted mice. Is there anything we can do to circumvent this problem?
Ben: So you found that in a state of caloric restriction NK cells actually appear to be subjected to some kind of a deleterious effect?
Dr. Clinthorne: Yeah, it was a very complicated process because natural killer cells are not uniformed. They are all these different sub-sets 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 and calorically restricted mice actually work really well and part of that was because they’re actually stuck it at 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’re looking at these respiratory virus and we were seeing that it was very lethal in calorically restricted mice, we eventually found 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.
Ben: Okay. Got you. Now, you mentioned to me when we’re 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 a 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 is maturation and homing important when it comes to NK cells? Why is that something that we would need to talk about?
Dr. Clinthorne: Yeah, I mean just like humans we all have to grow up, right? So natural killers 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 cells undergo something called 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 cells that they might encounter.
Ben: That’s why they call them licensing?
Dr. Clinthorne: Yeah.
Dr. Clinthorne: And so licensing all happens because not all natural killer cells will develop what we call an inhibitory receptor that’s specific to ourself. So inhibitory receptors are kinda disproves that natural killer cells used to probe the other cells that are around in the periphery and see what’s going on with them. And when you have an inhibitory receptors specific to self, it recognizes your cells as, “hey, this belong to me. These are part of my body. I don’t want to attack them.” And so really amazingly our bodies have given our NK cells an ability to become license 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.
Ben: Okay. So when an NK cell matures, it actually becomes license, it has this license to kill and at that point it’s able to act against this acute immune system assailants that you’re talking about.
Dr. Clinthorne: Exactly.
Ben: 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 of more like exposure to cancer, influenza, things along those lines?
Dr. Clinthorne: In the case of a natural killer cell we definitely talking about a transformed cells so that would be a cell that’s become infected by influenza virus or that’s transformed into a cancer cell.
Ben: Okay. Gotcha. So how does the NK cell actually work when it comes to identifying self versus non-self? Meaning, how does it actually learn to fight off something like influenza or something like cancer versus fighting off the body’s own tissues and what we would call an autoimmune type of reaction?
Dr. Clinthorne: 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 receptor gets a stronger signal will determine how the NK cell response. So if you’ve encountered just a normal heart cell, lung cell, you’re gonna get a really strong inhibitory signal and the NK cell won’t become activated. It won’t decide to kill that cell but in a case of a virally infected cell or a tumor cell, the activation signal is gonna be so much stronger because of uncolytic proteins that are being expressed on that cell surface. It’s gonna actually activate the NK cells, it’s gonna overwhelm that inhibitory threshold and now this license NK cells can go ahead and kill whatever they’ve encountered.
Ben: 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.
Dr. Clinthorne: Yeah, and they are gonna peeve the bone marrow, igress throughout the periphery, will have them in our blood, there’s a very large population of them in the lung as well, so about 25% of residence immune cells in the lungs are NK cells as well as pretty large population in the liver.
Ben: Okay, got you. 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 in the generation of huge amounts of lactic acid for example in the consumption of glucose by cancer cell. Is there any relation between NK cells and this idea of the metabolic theory of cancer 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?
Dr. Clinthorne: Yeah, it’s really interesting when you’ve actually looked at immune cell metabolism. Most people for a long time just figured immune cells have the same metabolism as every other cell but immune cell metabolism is becoming increasingly more important for understanding how immune cells become activated and worked, so a lot of immune cells actually used what’s called Warburg metabolism and that’s kinda the same metabolism that cancer cells used. So it’s kind of their way to work in the same environment that the cancer cell might be working. And so 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 functions, 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.
Ben: 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 embolism to allow it to actually fight a cancer cell but survive in the metabolic state that a tumor would be in for example.
Dr. Clinthorne: 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.
Ben: Interesting. Okay, so in other words, well, this bugs the question I supposed if someone were shifting to a ketogenic diet for example to control something like cancer, to shut off blood glucose from a cancer cell, wouldn’t you theoretically be shutting down the ability of an NK cell to function?
Dr. Clinthorne: You know, that’s definitely a concern. One of the unique things about NK cells is that unlike a key cell they don’t need proliferate and expand to respond, and that kind of what the metabolism used by T cells is really important for. So NK cells can just degranulate which is how they kill cells to release something called granzymes or reference that poke holes in their target cells and then they can die if they don’t have enough energy available but still they’re able to release and exert their functions.
Ben: Okay. Got you. That make sense. So, we obviously have pull 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 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 like, are there dietary factors, things that we can do in our diet that would either help or hinder NK cell function?
Dr. Clinthorne: 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 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 how dietary factors play in especially energy metabolism. And that’s kinda where my studies led me was looking at how different energy sensing pathways is within NK cells were responsible for the maturation and the function of NK cells which then kinda control their ability to home to different tissues.
Ben: And what have you found thus far in terms of dietary factors in NK cells?
Dr. Clinthorne: 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 a little bit simpler ways just kinda boost NK cell function without really messing with their development. And those include things like some of the glucans, these undigestible starches that are actually immunostimulatory, one that comes to mind that my dad left that a little work with was active hexose correlated compound which is a mushroom extract from shitake mushrooms. There’s some other glucans that come from other types of mushrooms that have been studied for boosting NK cell function.
Ben: Are there certain types of mushrooms because on the show I’ve actually interviewed a couple of folks who do things like dual extracts of chaga and reishi or who grow mushrooms like 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 extracts that are particularly effective at enhancing the function of NK cells?
Dr. Clinthorne: Yeah. It seems that the ones from shitake mushrooms are especially important and those are providing alpha glucans and there’s also some evidence that beta-glucans can do these too. And those are found in a few other types of mushrooms.
Ben: So shitake would be one good example.
Dr. Clinthorne: Yeah.
Ben: Okay. So, as far as something else that you mentioned in addition to mushroom extracts, I believe that you said this idea behind mTOR and calorie restriction appears to be favorable or unfavorable for these NK cells?
Dr. Clinthorne: You know, it’s really specific to 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 kinda trap them in a maturation 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 gonna be really good if you’re just looking for day to day NK cell tumor surveillance so that you wanna have really good NK cells that can float around throughout your bloodstream and look for tumor cells and kill those. Calorie restriction or intermittent fasting which both can inhibit mTOR are both gonna be pretty good for NK cells but you know, this is the contextual specific part, if you are at an increase risk of developing a respiratory infection, you really need to actually kinda push your NK cells into a more mature phono type and try to get them to home to the lungs ‘cause only these mature cells can get to the lungs to try to really provide respiratory defense and I think that’s where it kinda comes in handy for athletes because athletes are such a great risk of developing respiratory infections either when they’re training really hard or after really big events.
Ben: This is actually very relevant and important point I think. There’s a lot of literature that shows that when someone’s training for an event like when I’m training for Spartan or back in the days when I’m doing Ironman or I know that you’re an ultra-endurance athlete competing in all sorts of events, upper respiratory tract infection are a huge issue. Like just getting knocked out for a few days, being unable to train, and you’re feeling like crap when you do training or needing to stay aerobic ‘cause 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 either recovering from or protecting you from this respiratory infections, are you saying that intermittent fasting and caloric restriction would or would not be a good idea in this case?
Dr. Clinthorne: You know, what I would like to tell people is that you wanna eat a small healthy diet that’s going to more or less not over activate your NK cells, so this would be a diet that is gonna be may be intermittent fasting, using some ketogenic diet principles as a daily basis kind of diet and then when you really need to ramp 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’s really comes down to those times after a really really hard workout, right? We’ve all had that time we’re like, I really pushed myself and I got sick two days later. It’s after that big workout were you’ll 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.
Ben: And maturation would occur with actual feeding or with fasting?
Dr. Clinthorne: The maturation will occur with feeding. So it was really interesting how energy responsive to the NK cells. In our studies we just did simple refeeding experiment where we allowed our little caloric restricted mice to gorge themselves and it immediately boost their NK cells numbers of mature NK cells as well. So they are really really hyper responsive to this fluctuations and energy balance.
Ben: Okay. Interesting. So, a strategy then for an athlete who wanted to optimize 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 pot-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 citcumstances that would enhance your NK cell maturation I suppose.
Dr. Clinthorne: Yeah. 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 gonna help with your immune system but it’s also gonna help with your muscle recovery as well. And some of the biggest mTOR drivers out there are branched chain amino acid. So making sure you get that whey protein after your workout can really help drive mTOR to recover your muscles and help boost your immune function.
Ben: Interesting. Okay, cool. This is fascinating. So we’ve got things like shitake 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?
Dr. Clinthorne: 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 can gain that interplay again of exercise feats and immunology where resveratrol can boost NK cell function. Other beneficial things for NK cell function include…
Ben: Now just backing up there for a second with wine of course you often hear the complaints that the studies done on resveratrol would involve one needing to drink hundreds of bottles of wine to achieve that effect. Are you talking literally about a nightly glass of wine or are you talking about the actually resveratrol supplementation using some type of a pill or capsule or a powder or something like that?
Dr. Clinthorne: Yeah. I think you’re gonna wanna go with the pill or capsules or powders. The studies that are looking at these are using 1 mg/kilogram resveratrol which in human equivalent is quite a bit of wine, so I think you’d really prefer using this supplements.
Ben: Okay. So when you’re using something like resveratrol obviously that has a little bit of antioxidant or an anti-inflammatory effect, would you be concerned at all about that blunting the hermetic response to exercise if you are to take that on a regular basis for example at that dosage?
Dr. Clinthorne: Yeah, absolutely I would and I always recommend to people with antioxidant supplements to kinda leave ‘em 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 hermetic response.
Ben: Yeah. That’s certainly something that I’ve adopted the habit of. Only in a post-race scenario or when I’m traveling across many timezones and exposed to a lot of jet lag and airline radiation and toxins and pollutants and along those lines. That’s when I do things like Myer’s cocktail IVs or higher dose of resveratrol or liposome 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 outweight the cons but you’re saying that just because you’ve purchase a resveratrol supplement doesn’t mean you need to be using it on a daily basis and it may in fact be not such a good idea when it comes to exercise adaptations.
Dr. Clinthorne: 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.
Ben: Got you. Could the same be said for something like curcumin?
Dr. Clinthorne: Yeah. Well you know, that was another one that we kinda 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 seemed to be involved in some redox signaling and activating what’s called Nurf 2. Are you familiar with Nurf 2?
Ben: A little bit but go ahead fill our audience in line.
Dr. Clinthorne: So Nurf 2 is the master regulator of a lot of our endogenous antioxidants, our body’s own antioxidant responses. So when Nurf 2 becomes activated by free radicals or curcumin will then go down to the DNA and 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 kinda work on the backend by supporting our normal hermetic responses.
Ben: Okay, got you. So curcumin would be one strategy here and again being careful when that’s actually used and saving it for the more the difficult scenarios when you really wanna activate NK cell function and enhance your immune system. Resveratrol would be one, shitake mushroom extract, you talked about that a little bit, what else is out there that has an effect on NK cells?
Dr. Clinthorne: One of the hottest fields right now that you have to 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 need 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 functions. 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 are then trapped in the gut but they can travel throughout the body where they exerts 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 kinda 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 wanna look for strain that’s gonna 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 gasseri, lactobacillus casei, lactobacillus paracasei, or both are really important for NK cell function.
Ben: So what you’re saying is bacteria in the lungs can take cues from bacteria in the gut?
Dr. CLinthorne: Actually the immune cells in the gut that take cues from the bacteria gut travel to the lungs and provide protection in the lungs.
Ben: Okay. So by using a probiotic you actually can affect respiratory function?
Dr. Clinthorne: Yes, absolutely.
Ben: Interesting. That’s not something I’d thought too much about before and you’re saying some of these popular strains like lactobacillus or bifidobacterium would be appropriate for scenario like that? Like you don’t have to use some kind of fringe probiotic?
Dr. Clinthorne: I don’t think so. I think a lot of the researches focus on some of the most basic ones and they’ve seen good effects with NK cell function. If you Google probiotics in NK cell function, you’ll see a bunch of studies pop up that look at probiotic and seeing how it increases the ability of NK cells to kill when they just take blood from humans that are just taken a probiotic.
Ben: Got it. Interesting. Okay. Well, cool. That’s good to know. I use one called Probiotics Advanced right now and it has I think about 6 or 7 of the different lactobacillus strains in it and then something called GanedenBC, and I think there’s a streptococcus in there as well. So I think I’ve got my basis covered from the probiotics standpoint.
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Ben: And what about amino acids? You’d mentioned to me that there’s this concept of mTOR agonist 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?
Dr. Clinthorne: Yes. So you know, every cell in our body is gonna have an mTOR protein being expressed and when you consume the right amino acid specifically leucine which is one of the branch chained 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 cells, specific contacts we’re looking at maturation, we’re looking at increase in cytolytic function. So these cells are now able to be activated, so really making sure you’re getting your branch chained amino acids post workout, post really hard race even during races, this really is important for increasing mTOR activity. And I always tell people that branched amino acids are pretty prevalent in diet but if you really wanna get them looking at whey proteins and some other really high branch chained amino acid protein, supplements are a great way to go.
Ben: So very similar to overfeeding. This is not something you’d want to necessarily do constantly if you were coming at this from 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. If you were in a scenario where you needed to help your immune system as much as possible, assess recovery as much as possible, ditching the idea that you wanna called be hungry to be able to live a long time then you’d wanna increase the availability of leucine and this is where you could use a scenario like a branch chained amino acid or in my case, I actually use a whole amino acid and 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.
Dr. CLinthorne: 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.
Ben: Interesting. Cool. Okay, so is there anything else that from a dietary standpoint you would recommend that have an effect on NK cells?
Dr. CLinthorne: You know we’ve been talking about things to take to boost NK cell but there’s also a couple of 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…
Ben: Is this what you’d find in a cheap multivitamin for example?
Dr. Clinthorne: Yeah, exactly. And folic acid being the synthetic version, it doesn’t get converted into the active biological form very well. I’m sure you’re familiar with 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 seemed 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 measured 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 let your NK cells are functioning. And that was just observational study maybe 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.
Ben: It’s very interesting and this is something I’ve talked about for a while is this idea that if you look at a multivitamin and turn the label, there’s 2 things I look for to see if it’s a good multivitamin. Number 1, does it have high amounts of vitamin D in it not accompanied by vitamin K, and preferable vitamin A as well. Like it just kinda a whole bunch of vitamin D which a lot of multivitamin companies are doing now because vitamin D is kinda like the darling of the supplement industry but it has some toxicity with regards to calcification and when you take a whole bunch of it without vitamin K or vitamin A. And then the other thing I look for is the form of folate actual as you referred to methyltetrahydrofolate or it is 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 clicking add the cart button on the internet because it’s probably not that great.
Dr. Clinthorne: Yeah. Folic acid is one of those things that is kinda 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 quick in metabolizing it.
Ben: Okay. Got you. So avoid synthetic multivitamins that contain folic acid basically.
Dr. Clinthorne: Yeah, or your B complex. Take a look at your B complex ‘cause a lot of B complex has also have folic acid in them.
Ben: 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?
Dr. Clinthorne: 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 recommend contacting the manufacturer if it does say folate, 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 this methyl B vitamin supplements that contain methylfolate as well as methylcobalamin which is the methylated form of vitamin B12.
Ben: Got you. Okay, so we’ve got resveratrol and curcumin, probiotics, avoiding folic acid, ensuring that we get some kind of glycan from a good mushroom extracts, be smart about when we fast and when we feast, so these are 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?
Dr. Clinthorne: Yeah, absolutely.
Ben: Okay, got you. Now, what else from 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 studied?
Dr. Clinthorne: Yeah. It’s although 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. Timing your energy intakes to be in accordance with your energy expenditures is so important. It helps your metabolism balances so far 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 response. So making sure that you feed your immune system is just so crucial.
Ben: 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 work out and then feed? Unless you say it’s a typical workout, right? I think we’ve established the fact that after a very difficult soul crashing 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 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 enhance growth hormone or testosterone responses?
Dr. Clinthorne: Yeah. Now, I agree with what Mark is saying. I think that it’s really when we’re just kinda moving around or when we’re just kinda getting our workout in for the day that’s when it’s time to really take advantage of what intermittent fasting could do and at the same time intermittent fasting is also gonna 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 gonna 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 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 wanna take advantage of some of these concepts.
Ben: Got it. Okay, cool. Now, for you personally what would a typical kind of a harder training day, let’s say you’ve to take, for a lot of endurance athletes for example which I know you are, let’s say like a weekend, as a PhD of nutrition what would your typical day of eating look like in conjunction with the workout?
Dr. Clinthorne: Yeah. So I like to run really far, really long in the mountains. Really high and for me, I like to start my run fasted so I won’t eat anything. Wake up in the morning, get out the door, and we’ll usually run for 4,6,8, hours and 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, kinda 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, an hour and a half, that’s when I’m not gonna be trying to drive mTOR. I don’t really wanna overactivate my cellular responses, act those little responses. I want my body to be ready to respond off the big 8-hour days.
Ben: Got it. And what are you eating during your very long runs like that?
Dr. Clinthorne: I have to admit that it’s just about anything that I could find.
Ben: All right.
Dr. Clinthorne: A lot of times it’s gonna be just snacking on Trailmix, sometimes it a couple of Gu’s, sometimes I’ll just reach for a Snickers bar. I am kind of an 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.
Ben: Well, you’re certainly not having to worry too much about big release of insulin when you’re out there training but that’s something I’d talked about before to folks. I recommend things like exogenous ketones and amino acids and like a good digestable carbohydrate like a potato dextrin-based carbohydrate and then some electrolytes, mix into a water bottle or a flask for the very long workouts, and then I would do this during Ironman. I’d occasionally swing by the gas station and grab an ice cold Coke, 80 miles into a ride just ‘cause it’s freaking taste 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 coach my athletes is they’ll consume relatively reliable and clean burning fuels sources up until the point where I tell them they really need to pull the shoot in the race. That’s about the half Ironman or the half marathon mark of the Ironman where all the way up to that point is dietary management, staying relatively aerobic, and then 13 miles in you start to go hard and at that point I’ll tell them there’s one thing that you should drink and that’s Coke. The liquid Coke on ice at each aids station that you run by because at that point it’s like crack cocaine literally, but up until that point, you manage your diet. So yeah, it’s an interesting concept.
Dr. Clinthorne: Yeah. It’s time to put the fuel on the fire at that point, right?
Ben: Exactly. So, is there anything else that you wanna share with folks when it comes to NK cells, anything else you’ve discovered? Anything you have a chance to harp on you yet so far on our interview?
Dr. Clinthorne: 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 cells specific thing. You can really look at some of the things that you already be taking on your exercise regimen. Things like fish oil, things like phospholipids like phosphatidic acid or phosphatidylserine, branch chained 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 ‘cause you don’t have to go out there and spend a ton of extra money. This is something that 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 two benefits.
Ben: Yeah, and these are all practical things. I mean, obviously it’s not that difficult to find. The kind of stack we’ve talked about would be some type of shitake mushroom extract. And by the way, for those of you listening in, I’m gonna put a list in the show notes for the things that you could have on hand in your kits so to speak for the post hard workouts or the post races. Bengreenfieldfitness.com/killercells. Go to bengreenfieldfitness.com/killercells and I’ll have all these there.
But basically we’re talking about some type of like a shitake mushroom, some type of resveratrol, another that I have and also the multivitamin I use by Thorne, the resveratrol is called ResveraCel and then I think it’s just their Thorne multivitamin Elite is the one that has the methyltetrahydrofolate in it. Curcumin, and speaking of Thorne, they have one called Meriva which is… a lot of curcumin is notoriously poorly absorbed but in the phytosomal format, a lot of companies will use this 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.
Dr. Clinthorne: Yeah. That sounds like a good stack to me.
Ben: Cool. Alright. 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 at bengreenfieldfitness.com/killercells.
One last question for you Jonathan. Are you off to do any epic race or epic events coming up in terms of if you’re gonna take this 4-6 hour runs and bringing them into the streets?
Dr. Clinthorne: I’m planning on doing a circumnavigation [54:07] ______ in national park soon once the snows all melted out there. I’m looking forward to that and I’ve got a couple hundred milers on the fall. So, it’s time to get busy.
Ben: And you said a circumnavigation of what? You broke up for just a second.
Dr. Clinthorne: Oh, it’s a circumnavigation of Grand Teton National Park.
Ben: Oh! Interesting. Alright. How long would that be?
Dr. Clinthorne: Somewhere in the neighborhood of 35-45 miles. Depending on how lost I get.
Ben: Cool. That sounds amazing. Well, have a blast with that, man. And thanks for coming on the show and sharing all these stuff with us.
Dr. Clinthorne: Yeah. Thank you so much for having me.
Ben: Alright folks, I’m Ben Greenfield along with Dr. Jonathan Clinthorne signing out from bengreenfidlfitness.com. Head over to bengreenfieldfitness.com/killercells for all the show notes and to leave your questions and comments, and thanks for listening in.
My guest on today's podcast, Jonathan Clinthorne, PhD, has an intimate knowledge regarding the role that diet plays in immune function. Although it flies under the radar in nutrition science, the idea that certain nutrients can interact with the function of a type of cell known as a natural killer (NK) cell is very unique, an enchanting concept and certainly cutting edge, especially when you consider the role of mTOR activators such as leucine, and mTOR suppressors such as calorie restriction and intermittent fasting on NK cell maturation and function.
Dr. Clinthorne is an ultra-endurance athlete who was awarded his PhD in Human Nutrition from Michigan State University. He has served on numerous medical advisory boards and has been an author or coauthor on a number of research papers covering topics such as aging, caloric restriction, omega-3 fatty acids, probiotics, immune function, inflammation and human nutrition. When not working as the Manager of Scientific Affairs and Nutrition Education at Natural Grocers, you can find Jonathan running, climbing or skiing in the mountains of Colorado.
Jonathan happens to have an expert working knowledge of exactly to manipulate NK cell function on a daily basis to provide yourself with the most appropriate immune response for the season or around times of intense competition such as a triathlon or marathon, and during our discussion, you'll discover:
-How Jonathan discovered the intriguing link between NK cells and calorie restriction while studying human nutrition…[9:30]
-Why an NK cell needs to be given a “license to kill”, and how that can happen…[13:00]
-What keeps NK cells from destroying your own tissue…[15:20]
-How the active hexose correlated compound one can find in mushroom extracts are particularly effective for NK cell activation, and the type of mushroom that works best…[22:15]
-The link between intermittent fasting, caloric restriction and NK cell protection against respiratory infections in athletes…[24:30]
-Whether wine or resveratrol can activate NK cell function, and why they need to be limited to ensure the hormetic response to exercise isn't blunted…[28:50]
-How curcumin can be used correctly to lower the risk of flues and respiratory tract infections…[31:35]
-The fascinating concept of how the bacteria in your lungs take cues from the bacteria in your gut…[34:30]
-Why you should avoid folic acid and folate on the label of a multivitamin…[40:50]
-And much more!
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