July 16, 2020
[00:01:24] Podcast Sponsors
[00:04:34] Interview of Dr. Olga
[00:06:35] How To Refill Fat And Reshape The Extracellular Matrix (ECM)
[00:15:10] How Hypoxia Inducible Factor (HIF-1) And Breathwork Affect Our Sleep
[00:25:26] How To Mitigate Pexophagy
[00:27:56] Podcast Sponsors
[00:30:33] cont. How To Mitigate Pexophagy
[00:35:05] Circaseptan Vs. Circadian Rhythms
[00:39:50] Why NAD Supplementation Accelerates Aging
[00:43:30] How To Keep Muscles Young
[00:46:00] The “Daisy Cutter” Diet Protocol
[00:47:24] The Molecule That May Make The Keto Diet Impractical
[00:54:50] Closing the Podcast
[00:56:52] End of Podcast
Ben: On this episode of the Ben Greenfield Fitness Podcast.
Joel: Muscle growth, young muscle, and blood flow are one in the same. As blood flow decreases, as circulatory power decreases, muscle gets old. There's just a whole laundry list of checkboxes we want to do to make sure that we're adequately oxygenating during sleep, particularly in the brain. That's really where we got to jump on it. So, if we wanted to come at the very one thing we could do above exercise, above anything else to ensure that we live a long time, that we're in maximal health, we would have to correct this problem because what this problem touches on is —
Ben: Health, performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show.
Alright, it is time, high time for Part 2 with Joel Greene. I hope you guys liked the last episode with Joel. And of course, you can go to BenGreenfieldFitness.com and just do a search for Joel Greene to grab that episode with Joel. I would highly recommend you listen to Part 1 if you didn't because it will lay a lot of groundwork for what you are about to hear, although I've kind of recorded these podcasts with Joel such that you could listen to them in any order and still get a ton of benefit.
So, before we jump into today's show, many of you may be unaware of what I smother in my hair and on my skin every single day. Many people ask me about my skin firmness, elasticity, tone, glow, how I personally maintain that. I'm not saying that to sound narcissistic. I think genetically I also have good skin. My mother has beautiful skin. But I also take very good care of my skin. And in addition to doing a weekly clay mask from a company called Alitura, I actually interviewed the owner of that company if you go to BenGreenfieldFitness.com and you do a search for Alitura, A-L-I-T-U-R-A, you can hear that. After that clay mask, and every day in the morning and evening, I put a few tiny dabs of the anti-aging serum that I developed on my skin and on my hair.
I specifically formulated this with 12 different ingredients that are all organic and hypoallergenic to not only feed the skin's biome, something a lot of people aren't aware that they should be doing, but also to allow for the production of new collagen and elastin in the skin along with a ton of antioxidants for the surface of the skin, something especially important during sunny times. It does not smell like hippie juice. Actually, everybody, both males and females who use it become absolutely addicted to this stuff because it just feels so good on your skin, it smells so nice, it feeds your hair, it feeds your face, and it's called the Kion Serum. I'm going to give all of you a 10% discount on this stuff and you just go to getkion.com, getK-I-O-N.com, and use discount code BEN10. Little dab in the morning, little dab in the evening, throw a little on your hair if you want some extra, and it freaking works, and I'm super proud of it. I think it's one of the best beauty products out there if I don't say so myself.
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Oh, and one other thing, many of you commented on my approach or my attitude when Dr. Olga was psychoanalyzing me on a podcast last week. I think that some folks were even a little bit upset as to my potentially dismissive attitude towards her or at least felt as though I was being excessively critical. I will admit, I was very critical of what she was doing, and I will also admit that perhaps it is my hubristic nature that lends me or kind of pushes me towards resisting a little bit of this psychoanalysis. I've never been someone who could be hypnotized or who really did a very good job with like a therapist or a practitioner or someone like that, and I think some of that shown through in that podcast. I did not mean disrespect towards Dr. Olga. I was trying to strike a balance between putting her on a platform where she could give good information, but also being a critical question asker.
And I apologize to Dr. Olga, I apologize to any of you who felt as though I was being excessively dismissive or rude. After taking a listen myself, I could certainly see how it would come across that way. So, I am sorry. It is not my goal for this podcast to be negative, or to have negative energy, or for it to feel as though I'm trying to shame someone. That was certainly not the intention. But regardless, after listening again myself, I can see how it would come across that way. So, I am sorry for that attitude. I will proceed with a spirit of grace, not that I won't ask critical questions to my guest, but the spirit of that attitude I will certainly be hyperaware of in the future. So, that being said, I hope that that makes sense and let's go talk to Joel.
Based on this, it's a really big explanation and folks may want to rewind and listen again, but essentially, long story short is that we need to fix this issue by ensuring that we re-fill fat stores so that mechanical stress is relieved. And then, we also need to reshape that extracellular matrix so that we don't get this type of stiff collagenous fibers that can drive more of this so-called red team, these inflammatory populations in the fat. So, that being said, what would be the strategy to actually refill the fat and reshape the extracellular matrix? If it's one strategy or if it's multiple strategies, I'm sure people are going to be very curious about how to do this.
Joel: Yeah. So, just adding a little clarification to that, the body has got two options to fix the problem of fat loss. One is to refill the fat cells. We don't want to do that. That's not the one we want, but it's the one that is most likely. The other is to reshape the ECM. Okay. Now, reshaping the ECM is enormously energy-intensive. It takes a lot of energy, a lot of resources to do it because, for the most part, fat cells are relying on Warburg metabolism to do it. They're not pulling things into the TCA cycle. So, it takes a ton of energy. And during active fat loss, very often, the energy needed to reshape the ECM that's in there. So, what this gets us to is at the end of a fat loss phase, there's a pretty big list of new checkboxes that nobody's ever talked about that we need. So, we went through one of them, which is ticking off fibroblast growth–I can't get that one out, FGF21.
Ben: Mm-hmm. That's okay. The abbreviation works fine.
Joel: There you go, yeah. So, we want to tick off FGF21. So, we want to make sure that we do that. Along with that, what we want to do is we want to do a post-fat loss biome intervention. Okay? Meaning, there is a very large connection to the post-fat loss gut biome and the likelihood of weight regain. So, at the very end of a fat loss period, it's a very good time for a lot of the protocols that we've been talking about just to get in there and set the dials towards the lean phenotype because what you're going to find at the end of a fat loss period, particularly on the type of diet you've been using, particularly if you were leaning more towards the keto diet, you're going to find that a lot of the substrate in the gut needed for some of the healthier bacteria gets depleted.
And so, there's a whole school of research about this. So, you want to definitely do a post-fat loss biome intervention. That's one of the things that we want to look at. And then, there's just a host of other things that we want to do in that period, and you really have a window of time. It's roughly somewhere between four to eight weeks at the conclusion of a fat loss period. And there's a lot of new research on this. It shows that the maintenance phase, entirely different sets of genes get activated that promote weight gain, post-fat loss. And so, what we want to do is we want to get in and we want to be able to just tick down the list and knock these out.
So, for example, we would want to look at fatty acid-binding protein 4, matrix metalloproteinase-11, there's a bunch of very specific things that we'd want to do. And so, in this, it gets into immunology. And at the end of a fat loss period, for example, it's a great time for niacin. That's when you'd want to do pure, straight, makes me flush in uncomfortable niacin. So, in your fat mass, again there's that very special receptor, GDP 109 that is shared with butyrate in the gut. Well, it turns out that in your fat mass, that this is intrinsically linked to weight regain. And so, niacin at the end of a fat loss period is something that–that's when you'd want to use that for every day for about two, three weeks. And we can just keep going down the list and just checking boxes here. But it brings into this notion that there is a corrective period, post-fat loss, that we need to do. It's just like the analogy I used in the book is it's like a knee injury. If you injured your knee, you do rehab on the knee for six to eight weeks, post-injury, and you have to do this thing with your fat.
Ben: Right. And I would say just from my own personal experience the idea of resetting leptin with a high amount of protein at breakfast and even assuming like a long intermittent fast for a period of time, if you are leptin-insensitive, it's one really good trick. And I don't know if you're with me on this, but really paying attention to your collagen intake and getting a lot of really good bioavailable collagen, whether it's collagen fibers or some of these gelatin powders, things like that in the diet, seem to really help as well.
Joel: Yeah, 100% agree on both of those. In fact, sorry, I got into ranting without bringing up leptin. So, one of the most crucial things at the end of a fat loss period are these leptin interventions, and you'll see them in the book. But basically, long story short, there's really good research about massive breakfasts periodically at the end of a fat loss period, massive amount of carbs, massive amount of protein, some fats, but it's the calories, sheer size in the meals. You're getting 1,000, 1,500 calories in. And what this does is we're short-circuiting the leptin spike or leptin deficiency loop. We're driving leptin up at the very end of a fat loss period, which is normally not what happens, and this helps to mitigate that particular aspect of it. And then, yeah, 100% on the collagens. And glycine, collagens, all that stuff, very, very useful.
Ben: Yeah. And then, one other thing related to the inflammation component, I was pleased to see you get into this in the book, and that's shutting down some of these inflammatory signals that visceral fat in particular can produce. And one thing that we already discussed, the high amounts of glycine with something like that pre-bed Jell-O seems to reduce visceral fat pretty significantly, and reduce some of the oxidative stress that that can produce. But then the other one is molecular hydrogen, and you actually get into the fact that you, like me, have met Tyler LeBaron, who runs the Molecular Hydrogen Foundation, and that hydrogen can actually enhance one of the key molecules that suppresses intramuscular fat, which can contribute some of these issues that we were talking about. So, I mean, throwing in like–I do a big mason glass jar full of hydrogen water in the morning and in the evening. I think that's a pretty good strategy as well.
Joel: Yeah. You see, I do the hydrogen–yeah, 100% lockstep with you in this. I feel like we've been running down parallel paths apart all these years, but yeah. The molecular hydrogen–first of all, about Tyler, good [00:13:20] _____, I met Tyler like back in 2015. I've met a lot of empty suits in this business. I met guys that should know everything and they don't really know nearly what they should. And again, I just always see myself as a consumer, like I'm just a consumer and I want to believe in you, I want to believe you're this thing, and I've been disappointed more often than not.
Joel: But man, I'll tell you what, Tyler and I got into it at this trade show and, holy cow, like–I mean, that guy knows his stuff.
Ben: Yeah. Super smart. I have an interview with him too and I'll link to that in the shownotes for you guys if you go to BenGreenfieldFitness.com/joelgreene2. I've done a few podcasts on hydrogen and I'll link to those in the shownotes, but yeah. I mean, you detailed this in the book quite a bit, but I think long story short, because I want to give us a chance to talk a little bit about sleep and a little bit about anti-aging, two other areas that you dive into in the book, but it turns out that when it comes to fat loss in particular, mitigating some of the inflammatory effects that occur from cycling fat loss, you got to have a few of these ducts lined up in a row, like resetting leptin, like paying attention to some of this mechanical remodeling and collagen intake, molecular hydrogen to shut down some of the inflammation, cold thermogenesis within reason, and then some of these timing parameters in terms of the protein and the prebiotic fibers or the fibers, in particular, pre and post these larger meals. It's just this whole system that once you implement doesn't involve you spending an hour to get ready to say like, “Have a slice of cheesecake,” but instead, incorporates these natural habits that you're weaving in. So, again, like the book gets into a lot of this in even more detail, but I'm hoping to give people–whether or not they get the book, some really solid takeaways here.
And so, that all being said, let's turn to sleep. It's no secret that I'm a huge fan of breathwork. I'll do like 4-7-8 breathwork prior to sleep. Sometimes I'll do carbon dioxide retention protocols, and box breathing and things like that in the sauna followed by a quick cold shower or cold soak prior to sleep. But you get into one particular molecule that I find fascinating in the book, hypoxic-inducible factor or hypoxia-inducible factor, HIF-1. Explain what HIF-1 is and how that relates to sleep, like, why should people care about HIF-1 and breathwork, particularly in relation to sleep?
Joel: Well, so let's think about something here. When you look at the machine that is your body, energy production and life are one and the same, meaning that if energy production stopped in your body, you'd be dead right now, like, within five seconds, you'd be dead, okay, if your body wasn't producing energy. You cannot differentiate the production of energy from life itself. In order to make energy, you need two things. You need substrate, meaning, you need a fuel source, so you need glucose, you need ketones, you need a fuel source, and then you need oxygen. Now, think about something. Your body has several redundant backup mechanisms if it doesn't have substrate.
So, like, if you don't have food, then well, you can deplete liver glycogen, you can deplete muscle glycogen, then you've got your body fat. Then if you're done with all that, then you can recycle spare parts from yourselves. You got all kinds of backup mechanisms. What are the backup mechanisms if you don't get oxygen? Well, there's just really one and it's hypoxia-inducible factor. And hypoxia-inducible factor–again, I built my book around two concepts, central to immunity, which are macrophages and HIF-1. When you start to look at this, you cannot define how the body works apart from these things, you can't.
So, what hypoxia-inducible factor is, it is a–think of it as like a tension switch. So, what it does is it's a tensioning mechanism. It's kind of like the coupling between a train, two cars and a train that allows some give and some take. And so, when there's no oxygen available, you need a mechanism to allow your body to survive in the presence of no oxygen. That's HIF-1. It's the backup mechanism when there's no oxygen. And the way that it works is it basically turns off OXPHOS, turns off the TCA cycle. So, the mitochondria need all kinds of oxygen, and basically shuts that down, lets the cells in question use Warburg metabolism temporarily, and all's good, it's great. Now, the thing with hypoxia-inducible factor is normally, it dissipates, it's ubiquitinated very quickly within the cytosol, within the cell. But there is a condition called hypoxia, and there's different types of hypoxia. The one we need to concern ourselves with is called cyclic hypoxia. And what we see with cyclic hypoxia is that it tends to happen during sleep a lot for most people. Okay?
Ben: Mm-hmm. And we're talking about elements of hypoxia during sleep even if you haven't been diagnosed with, say, a full-blown sleep breathing-related disorder. A lot of people are having these hypoxic excursions during sleep?
Joel: Yeah. And when we say hypoxia, we just mean that the cells in your body, whether in certain tissues, particularly the brain, or certain organs are not getting quite enough oxygen. Now, this is not necessarily an abnormal thing, we all get lack of oxygen, and this mechanism is in place. But here's the thing. Here's the reason we can't ignore this. And really, it's a game-changer. What you have to understand is that Warburg metabolism, meaning, using just glycolysis has a unique chemical signature wherever it's found. What we see is that when cells go into this, they tend to consume lots of glucose and they tend to output lots of free radicals and lots of nitric oxide.
Now, in particular, immune cells do really well, some of them do well in a low oxygen environment, in particular, the M1 or the red team macrophages, the inflammatory guys, they do well. But the problem is is when you get too many of them, what happens is you're getting this chemical signature that profiles 100% identical to cancer. In fact, there's no difference. In fact, I left a chapter out of my book on this. I called it Death Con 1, the chemical signature of death. And so, what you find is that if we're going to talk core health, core immunity, core aging, you can't get away from the presence of oxygen, and oxygen being properly disseminated in your cells because what happens is when cells begin to suffer chronic hypoxia, there's a very interesting thing happens, and this happens during sleep. And essentially, what happens is normally inside your cell, hypoxia-inducible factor, it just gets broken down, it gets ubiquitinated, and we get rid of it.
But what happens is when you're suffering hypoxia, there's this daisy chain of enzymes, prolyl hydroxylase, von Hippel protein, all this stuff, that touches on the mTOR pathway, the growth pathway, cellular growth. And what it does is as, within the cell, the cell gets oxygenated and then deoxygenated. Well, just think of two dials. One is the dial controlling oxygenation and deoxygenation, and the other is the level of HIF-1 in the cell, and they both start bumping up and down and bumping up and down. But what happens is HIF-1 starts going up and up and up because it doesn't know where to sits. And eventually, what it does is it stabilizes in the cell, so it sits there permanently, and then it goes into the nucleus and it activates all these oncogenic genes. Most of them nothing good.
And the reason this is all so important is the place it tends to most happen is sleep. And so, if we wanted to come at the very one thing we could do above exercise, above anything else to ensure that we live a long time, that we're in maximal health, we would have to correct this problem because what this problem touches on is basically substrate metabolism of immune cells. And substrate metabolism of immune cells changes the way we think about metabolism. The old paradigm metabolism is just my metabolism. I got a good metabolism, I eat, blah, blah, blah. In an immune-centric paradigm, you've got to think about the metabolism of immune cells because when the TCA cycle gets shut off, you get activation of all these lipogenic genes, genes that store fat, genes that activate all these other things like reactive oxygen species and do all these other things that affect the entire body and recruit immune cells into this inflammatory storm. So, sleep is the place where we need to begin to knock this out. And so, that's why it's so important.
Ben: Okay. So, in a nutshell, this HIF-1 is a way that–basically, it's a protein, it's going to accumulate in periods of pseudohypoxia, which would in particular happen during sleep. It would do things like enhance aging or accelerate aging, upregulate inflammation, and result in a host of side effects that would dictate that high levels of HIF-1 protein are going to be something that's not only disruptive to sleep but disruptive to longevity in general. And that all being said, how would we actually downregulate this HIF-1 protein? Like boots on the streets, what are some practical ways that we could clear HIF-1 from tissue, for example, or activate HIF-1 when it needs to be activated?
Joel: Let me give you the high level and then we'll just break down three or four methods. So, high level is you need to learn how to steer macrophages, and it's kind of a core concept in the book, but long story short, you need to learn how to steer populations of immune cells, macrophages, from the inflammatory to the anti-inflammatory. And the way you do that is tissue by tissue and the protocols are unique to each tissue. That being said, here's just some specific stuff that we can do. So, one of the ways that we can spin down hypoxia-inducible usable factor is with niacin and zinc. And so, by taking these two things at bedtime, it's going to spin them down a little bit.
We can add into that a protocol after doing that where we use exogenous ketones, which is going to actually spin HIF back up a little bit, but it's not a bad thing, it's a good thing, it's kind of a compensatory mechanism. Niacin clears HIF-1 from different types of tissues. Another way that we can do this, and I talked about this at length in the book, is during a fast, we want to, A, fast, B, take omega-3s, C, take niacin, take all those three together. Now, on their own, all three of these things will help clear excess HIF-1. But together, during a fast, it may be extremely useful for that particular aspect of clearing excess HIF-1. HIF-1 is not all bad, it's fantastic post-workout. You want to make more of it when you're working out.
Ben: Which is why things like nasal breathing, for example, during a workout would be a good idea, or avoiding hyperventilation during a workout would be a good idea based on the teachings of guys like Anders Olsen or Patrick McKeown, and you want some elements of carbon dioxide retention and hypoxia during exercise to drive up HIF-1, but then you'd want to drive it down or back down, particularly when you're getting close to something like a sleep cycle.
Joel: Yeah. Really, sleep is the first thing we want to go after. And so, there's just a whole laundry list of checkboxes we want to do to make sure that we're adequately oxygenating during sleep and preventing the accumulation of HIF-1 during sleep, particularly in the brain. That's really where we got to really jump on it.
Ben: Yeah. Another thing that you say happens during sleep is something I don't think–there's two terms you use in the book that not many people are going to be familiar with that I want to also unpack. One is pexophagy and one is circaseptan rhythms. So, you say something called pexophagy occurs during sleep. What is that? And if it's good, how would we actually accelerate that or maximize it during sleep?
Joel: So, pexophagy is selective autophagy of the peroxisomes. And peroxisomes are these little organelles within cells that do a number of things. The two primary things they do is they break down the long-chain fats, the omega fats, and they also maintain basically hydrogen peroxide balance within the cell. And there's an emerging body of research and I would say a paradigm shift that is underway, and it's shifting us from this idea that the mitochondria are everything in terms of longevity, and aging, and energy production to probably a more accurate approach that the mitochondria are co-equals with the peroxisomes in terms of all the things I spoke of. They're like the twin pedals of a bike. Their operation is so intrinsically linked. And the way that they make energy, and the way that they keep the cell healthy, and the way they keep us young is so intrinsically linked that we can't separate them.
And so, it turns out that peroxisomes working the way they should has a whole heck of a lot to do with not dying, and being healthy, and aging well. And what happens with age is that the membrane of the peroxisomes begins to stiffen up. And these key proteins, PEX proteins, don't pass back and forth readily between the peroxisome membrane and the internal area in the peroxisome. And so, when that happens, you get an imbalance of free radicals in the cell, you get an imbalance of hydrogen peroxide in the cell. And this leads to this daisy chain of cascading effects that essentially just kills the cell and kills you. So, keeping peroxisomes healthy by the induction of pexophagy, meaning, we want to clear peroxisomes, is something that really hasn't been looked at and it may just be as important as mitochondrial biogenesis. In fact, I believe that it is. We're going to wait and see as emerging research comes about, but there's a small body of a very good thought on this and it makes a lot of sense when you dive into it.
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So, that's pexophagy. Basically, what we're trying to do is steer peroxisomes via basically forcing them to go into pexophagy, which is almost like an autophagy-based mechanism that is targeting these inflammation producing peroxisomes, or essentially making new peroxisomes while clearing out old ones, and we want to do that while we're asleep. And so, what would be the actual strategies we would use pre-sleep to amplify that so-called housekeeping effect?
Joel: There's a couple of ways that we can look at initiating this. It seems to be that, and this is this is super, super cutting edge, but it seems to be that food patterns may be the best way to do this. So, the thing about peroxisomes is that we need them to burn long-chain fats. That's what they're needed for. And peroxisome proliferation, PGC-1alpha, and all these sort of longevity kind of terms are at the forefront of youth and anti-aging and all this stuff, getting peroxisomes to proliferate in activating the very specific receptors and all that stuff.
Well, so what it looks like is that periods of fat feeding, particularly giving the body omega-3 fats initially so that the peroxisomes need to spin up, we need to make more peroxisomes to handle the omega-3 fats, and then slamming after a couple days into stearic acid, into omega-9. And then at the end of maybe four or five days, slamming into a high-carbohydrate meal may just be the thing that induces peroxisome proliferation. And in particular, if we can do this around bedtime, then it may just be the case that this is what drives pexophagy, and it makes sense if you look at it. So, there's some good research here that shows that after prolonged fat feeding, the job of the peroxisomes is to break down fats. If you slam a big carbohydrate load in the body, you force pexophagy on cells. And so, these feeding patterns and understanding sort of the timing and all that may be the go-to maneuver.
Ben: Okay. So, you talk about, for example, magnifying butyrate production while you're sleeping at night by loading the gut with resistant starch, not at dinner, but at lunch as one way to enhance pexophagy. So, consuming resistant starches with lunch appears to have this effect, and then you're also–probably one of the other really big tips that you gave in the book is to take some type of omega-3 oil and some type of berberine prior to bed to actually enhance the pexophagy even more during your night of sleep to make new peroxisomes and clear out old ones as you're sleeping.
Joel: Well, clarification, I think the way I have that in the book is the resistant starch and all that stuff is to drive butyrate production while you're sleeping to drive bifidobacteria. The whole pexophagy thing is another module, like something you want to throw in maybe once a month, which would be over a period of about four or five days, sustaining high-fat feeding from omega-3s then switching to omega-9 stearic acid. And then finally, at the end of that, having a day where you slam into carbohydrates, particularly like a bedtime, like a big carbohydrate meal then. So, what's going to happen is all of the things that we think of is like pro-longevity, autophagy, all that is going to stop. And then, the peroxisomes are no longer proliferating. In fact, we've got to clear them out. And so, the cells now have a substrate metabolically speaking, a very large imperative to get rid of like the old dirty peroxisomes.
Ben: Yeah, yeah. And then, the other thing, and that may sound like a little bit more of an advanced protocol, but you lay it out really well in the book. Again, this is stuff that can be simplified and introduced as habits like brushing your teeth once you wrap your head around it. I took a couple of weeks to read your book just because I had to really wrap my own head around everything you were talking about. Now, I'm slowly implementing. But again, if you're listening and a little bit of that went over your head, also grab the book so that you're able to systematize this. And for the part of the podcast, you're listening to now, we're into Part 2 now. So, go to BenGreenfieldFitness.com/joelgreene2. That's BenGreenfieldFitness.com/joelgreene2. And then, Part 1, you'll find it at BenGreenfieldFitness.com/joelgreene. And in both cases, Greene is spelled with an “E.”
One other thing I want to talk about related to sleep is this idea of circaseptan rhythms. What's a circaseptan rhythms? Because that's another thing that's really not a term that I've heard used very much until reading your book.
Joel: So, it's an older area of research that has sort of gained new attention due to immunology. And there's a subset of immunology called chrono-immunology, which is related to the timing of the administration of drugs. And what is bubbling up is this notion that certain days of the week are better for certain things, and that at least in the field of chrono-immunology that they can get 100% difference on the impact of the administration of a drug just by timing it to the correct day of week. And so, it gets to this notion that is really fascinating that seven-day rhythm is bound up into the biology of everything, whether it's a spider or a bacteria or a human that these seven-day rhythms seem to play out.
And within humans, it's kind of interesting. For example, sodium retention seems to work on a seven-day rhythm that's independent of sodium intake. I mean, that's crazy when you think about that. Or another example would be like cortisol levels seem to work on a seven-day rhythm peaking on Mondays, which is why people die on Mondays, or with respect to cardiac rhythms, they seem to reach their nadir on a Wednesday. And in the field of chrono-immunology, there's this whole thing about heart attacks happening on Wednesdays, all this stuff.
Ben: So, fascinating.
Joel: It's super fascinating, yeah, yeah. In fact, in my VEEP System since 2009, we've done this, which is this notion that to get beyond the macro calorie thing, it's the idea that unique days of the week have unique nutritional requirements. You don't have to be a rocket science to grab onto that. It's kind of like think about it. Well, do you eat the same on Monday that you eat on Sunday?
Ben: Right. Sunday for me is a super relaxing day, and Monday is like super high stress go, go, go.
Joel: Yeah. And so, when you start to go down this rabbit hole, we come up with this whole new thing, and it's tailoring nutritional inputs to circaseptan rhythm. For example, Monday. Monday is like giant cortisol day. So, there's good and there's bad to that. There's things that we can do that are–we can ameliorate cortisol production–what a lot of people tend to do, what I see a lot of–and I did these corporate wellness engagements for years and years where–we didn't deal with fit populations, we dealt with like employee populations, and very large engagements, thousands of people. And what you see a lot of is people come into Monday and they really want to get on the plan and do great, and they do pretty good 'til about four o'clock, and then they come home and drink wine and eat carbs. The reason is they're stressed out of their mind and they need to blow some cortisol off, and that's how they do that. I mean, this is just we do a whole show on this, but it's really fascinating looking at tailoring inputs to this kind of thing.
Ben: Yeah. And I would say if folks begin to look up circaseptan rhythms, you can find out which days that you're prone to specific issues such as the cortisol to DHEA ratio being highest on Monday. So, stress and depression are going to peak on a Monday. Therefore, Monday being higher in stress, and you get into this in the book, might be a day to do things like prioritize a lot of flavonol and polyphenol-rich foods early in the day to drive your vitamin B production to counteract stress later on in the day, and then use something like an EPA oil in the evening to drive down stress-induced cortisol at night. It's fascinating to begin to look at the week rather than the day and actually adjust your nutrition intake based on which day you're on. I mean, we're getting into some kind of advanced and nitty-gritty, almost like biohacking of one's weekly rhythm, but yeah, it's fascinating that we have the circadian biology, and then also the circaseptan biology. And I thought that was just a really, really interesting insight in your book.
Joel: There's also a seasonal biology, and there's good research on this. So, during the winter, we tend to sleep more, we tend to have greater issues related to heart attack and all kinds of things during the winter. So, there's daily rhythms, weekly and seasonal rhythms, and factoring all these things in there is kind of the next level.
Ben: Yeah, yeah. Okay. So, I know we're beginning to run up against time, but I would be remiss not to perhaps, and if you're game, maybe rapid fire a few questions regarding anti-aging at you. And these would be things–you can keep your replies pretty brief if you would like, but I want to ask you a few quick questions.
And this flies in the face of what a lot of other folks will say. You actually say that NAD supplementation may actually accelerate aging. That's going to surprise a lot of people. How would that actually be?
Joel: Quick answer. If you're younger like 30s, don't worry about it, if you're older, take it very seriously. Basically, long story short, one of the things, perhaps the biggest thing driving aging is populations of immune cells and immune cell signals because they accelerate the inflammasome. And the thing to understand is that immune cells are cells, they're cells, they have the same energy requirements that cells have. And immune cells in particular express very specific types of receptors, they're called the CD receptors, and this is a whole thing that is like an endless rabbit hole of fascinating stuff. But long story short, there's a particular receptor on very specific types of immune cells that gobbles NAD. It's called CD38. And so, if you are in the inflammaging portion of life or you're dealing with chronic inflammatory issues, there's a protocol, there's an order of operations and research papers are starting to address it, before you take NAD, you want to spin down all of the inflammatory markers because if you don't, NAD feeds the immune cells, it makes it worse.
Ben: Right. And this would be related to this whole concept of senescent cells. There's these studies on things like quercetin and danasitib I think is the pharmaceutical used to target senescent cells. And everybody who I've talked to in the anti-aging field has said, “Well, you're going to need those senescent cells when you're young.” And so, in the same way you wouldn't want to overdo NAD supplementation, one could argue that a very active, inflamed, or a person who's flying a lot on airplanes, exposed to a lot of EMF, et cetera, could probably benefit from the DNA repair mechanisms induced by NAD, in particular, combined with sirtuins.
But even then, more is not better. And this idea that as you age, NAD would become more beneficial in the same way that as you age, some of these senolytic compounds would become more beneficial, is a concept that makes just as much sense as the idea of consuming more, say, protein-digesting enzymes as you age, but your body changes as you age. And so, that also made pretty good sense to me that NAD supplementation should be moderated early in life, and then later in life, especially–I would say probably post-50 years old based on some of the data I've seen, that's when you begin to start to target some of these senescent cells with things like higher dose quercetin or NAD supplementation or something like that.
Joel: Yeah, very much so. I would offer there's an order of operations. You first want to initiate [00:42:41] _____, you first want to spin down an inflammation, that's a whole topic, and then apply NAD. You don't want to be like super inflamed and then begin taking NAD. And even though you might see some improvement, you might say, “I feel a little bit better,” but there's a push-pull to it. So, again, it's not so much that NAD is good or bad, it's what, when, and how.
Ben: Right. Now, you explained fat loss and the damage that occurs to the extracellular matrix when we're constantly remodeling these fat cells and doing weight loss cycling. And similar to that when it comes to muscle cells, there's this idea that working out, especially these really intensive bodybuilding style workouts or eccentric workouts like CrossFit workouts, for example, create these micro-injuries that often can accumulate and result in what you call old muscle.
And you've got this key idea in the book that one way to keep muscles young is to clear muscle damage. Do you have any targeted tips for based on where someone's at in life, how they should work out to maintain young muscle versus just building old, inflamed, adhesed muscle?
Joel: Boy, that's–gosh, I'll do my best on this one. It's such a huge topic. I'll do my best to condense.
Ben: It's okay. Just give us your key takeaways. And you may be even skipping a lot of the science behind it. Just get into some of the practical takeaways, some of the deep sciences in the book of course.
Joel: Yeah. So, the people who would already know this are high-level bodybuilders. They already know this, like they all get what's called bodywork, and they get some dude that goes in and finds those muscle adhesions and very painfully just gets them out. And so, what you find happens is–and if you talk to people that do this, they stay pumped, they have young muscle. Their muscles get pumped, it does the things it did when it was young. Conversely, if you're not doing that kind of thing, what you find is you can work out, but you can't get pumped and all these other things. So, the addition of very specific types of massage post-workout at very specific periods, I would say about six hours' post-workout, and it has to be very deep tissue, and it has to be in conjunction with a couple of other things that stimulate blood flow and blood circulation would be the first thing on the list. Muscle growth, young muscle, and blood flow are one in the same. As blood flow decreases, as circulatory power decreases, muscle gets old.
Ben: Yeah. And that's why I think one of the best things you can do. So, I get a weekly two to three-hour massage, and then every morning, 10 to 15 minutes on the foam roller. I've got Kelly Starrett's “Becoming a Supple Leopard” like a cookbook next to this wicker box that I have just full of all these different balls, and rollers, and toys. And I think, as you've alluded to, these adhesions are one of the big things that creep up, especially in very active people along with the issue of the blood that you get into in the book, and the young blood versus the old blood, but yeah. I mean, in a nutshell, taking care of the blood via specific use of some of the minerals and the vitamin C that you talk about while also engaging in–I think the biggest thing is just regular use of deep tissue massage and foam rolling. And just getting just as comfortable with that as you are with working out is I think one of the best ways to maintain young muscle, and you definitely get into that in the book.
Quickly explain, when you say daisy cutter, because you've said that a few times during this interview, what do you mean when you say, “daisy cutter”?
Joel: So, the daisy cutter is just a diet protocol that I've been using for a number of years and it's the most brutal thing you'll ever do in your life. If you have gut issues, you have any kind of issues with fiber gut, don't do it. It's only if you have like a very solid gut. But basically, long story short is you want to flood the gut with massive amounts of very specific types of hemicellulose and cellulose, things found in green beans, things like that, for example, and a lot of it. And at the same time, a whole bunch of protein and no fat.
Ben: And how often do you do that?
Joel: Not very often. You'll burn fat like crazy on it and you'll force the body to make just a boatload of butyrate. So, you'd want to do it in the evening leading into like sleep, and it works like crazy. It works really good, it makes your poop not smell, all these great things. It's super, super hard, super hard because what you're doing is you're getting this big bolus of these fermenting fibers in the gut, you're not getting any fat, so there's no satiety, and then you're getting all this bifidobacteria production. And so, it's great for fat loss, it's great to kind of retune the gut here and there, but it's very, very difficult to do. So, it's kind of like here and there. You might want to throw it in there.
Ben: Okay. And then, I promise this is going to be the last question I ask you, and then there's like a billion questions I could ask you, but I would be remiss not to bring this up because you talked about it in your book. And with you knowing this is the last question, you can take as deep a dive as you want, but ketosis, and a ketogenic diet, and your take on that because you have a very unique take on it and you are actually someone who warns people against this ketogenic diet, particularly based on this very special molecule called 4-HNE. So, explain what 4-HNE is and why, based on that, you would want to be careful with the ketogenic diet and what the proper approach for ketosis would be.
Joel: Yeah. So, the main thing that in the book I offer with the ketogenic diet, first of all, I've used keto protocols for years, they're in my VEEP System. They're extremely beneficial. They're highly functional toolsets. I mean, it's kind of like the tool you take your oil off in your car like you have to have the thing. So, they're very, very essential, and they're very useful, and they're very pro-life extending in a lot of ways. The issue that we get into is overdoing it, sustained, long-term sort of keto diets. That's where I bring up the issue. So, I don't have any issue doing them short-term, couple months, six months, half a year. So, here's the mechanism. One of the mechanisms by which keto diets work is that within the mitochondria, they increase oxidative stress.
Ben: They increase oxidative stress.
Joel: They increase oxidative stress short-term within the mitochondria. And then, there's a hormetic response so that mitochondria upregulate production of glutathione and all these sort of like compensatory mechanisms. And so, then what you see is that oxidative stress across the body goes down. And so, you see this improvement in the parameters of oxidative stress. And again, I'm just mapping this with time, and that's the real thing, is when we make these statements like keto diets, lower oxidative stress, my question is at what point in time? So, what you'll see is this initial increase in oxidative stress due to fats being oxidized within the mitochondria. And then, you see a counter effect sort of in the mid to long-term. And you see oxidative stress go down. But then, over time, what begins to happen is the mechanism that's mediating the oxidative stress is what's known as an electrophile. An electrophile is a highly, highly reactive molecule, highly reactive. And the issue with this electrophile, it's called 4-HNE, 4-hydroxynonenal, is that it's happening within the mitochondria.
Ben: Same thing, by the way, 4-HNE is produced in massive amounts when you drink alcohol?
Joel: Yes, absolutely. It's why alcohol drinkers look old. It's 4-HNE. But what you see long-term within the mitochondria is you begin to run into the potential to damage a very special fat cardiolipin within the mitochondria. So, as you're pushing fats down the TCA cycle, what you'll see is that damage to cardiolipin can begin to accumulate as levels of 4-HNE accumulate within the mitochondria. Now, cardiolipin basically gives the mitochondria their ability to bend. And if the mitochondria can't bend, then they explode.
So, the issue that definitely is something to be aware of is that long-term, there's an uptick in 4-HNE. And as you see 4-HNE increase, then what you need to do is you need to look at the type of cell, and the duration, and the concentration of 4-HNE. And it has different effects in different types of cells. So, in cancer cells, in certain types of cancer cells, in small amounts, it kills them, kills cancer cells, and that's one of the mechanisms keto diets work. In other types of cancer cells, it diffuses them to adjacent cells that don't have cancer and helps cancer spread. In not cancer cells, 4-HNE in low amounts is beneficial. It helps lower oxidative stress. But in non-cancer cells in higher amounts over sustained duration, it can cause damage within the mitochondria.
And there is now just beginning to emerge research, and it's still in the animal stage, but showing that sort of these long-term keto diets may be inducing damage within the mitochondria. And it just gets to this thing of like–there's this belief that you have this–again, you have these polarized beliefs. You have one belief that, “No, ketone bodies are the body's rightful natural fuel source,” and the other side is, “No, glucose is essential.” The truth is if you have too much of either one, you're going to get issues. If you have too much glucose, you're going to have problems. If you're just burning fat all the time, you're going to see issues with insulin sensitivity and all these other things. They need to be balanced out.
Ben: Yeah. One of the things you get into the book, for example, is 4-HNE can switch off a key protein that inhibits breast cancer. It can be implicated in gastric cancers and prostate cancer. And so, there are certain cancers in which you probably want to do your research before you say, “Okay, I have such and such a cancer and I'm going to switch to a ketogenic diet,” when in fact, driving 4-HNE production may in fact drive the growth of that cancer. And so, again, you unpack this really elegantly in the book, but once again, it points out the fact that the perfect diet in one scenario may not be the perfect diet in another scenario.
And this idea of 4-HNE and a ketogenic diet, I think anybody who's following a ketogenic diet needs to read this section of the book and really make sure you're very familiar with the mechanism of action via which this 4-HNE works, and that you're careful with sustained long-term strict ketosis in particular. I personally am in a state of nutritional ketosis based on just physical activity and carbohydrate mitigation much of the time, but I cycle nearly every day. I mean, I'm eating 150 to 200 grams of carbohydrates every single night to cycle back into carbohydrate utilization, refill glycogen stores, give myself adequate glycans for joints, et cetera, and I find that model to be very sustainable. And as you really layout quite well in the book, one of the worst things you would want to do if you're on a ketogenic diet that's already driving 4-HNE production is, A, drink alcohol in any appreciable amount, or B, eat fried foods because both of those are going to drive 4-HNE through the roof. So, all the more if you're on a ketogenic diet, I think you call it the stupidest thing you do at ketogenic diet, is to drink alcohol and eat fried foods. I mean, I'm not opposed to like a glass of organic wine with dinner, but yeah. I mean, like binging on alcohol or having certain periods of time you're getting drunk or not being ruthlessly cogs with a vegetable oil intake, especially all the more so, if you're on a ketogenic diet, yeah, I mean, that's bad news bears.
Joel: Yeah. I put that in there because like in the real world, what you see a lot of is people who are like strict ketogenic diet, people, during the week and on the weekend, they go party. Well, okay. Again, I can hear the pro-keto peeps just hollering right now. Look, I'm very pro-keto like short-term. I think it's fantastic. It's highly functional. It's the long-term sustained thing with keto that you need to think about. And in a practical sense in the real world, it's this whole thing of like you're going to go out in the weekend, you're going to drink and eat fried food, like all those things together, not smart.
Ben: Yeah, yeah. Well, we kind of, in two podcasts, the first part you guys listening in at BenGreenfieldFitness.com/joelgreene, Greene with an “E,” and this second part at BenGreenfieldFitness.com/joelgreene2, like BenGreenfieldFitness.com/joelgreene2, we kind of scratched the surface of everything that's in the book, but I'm hoping we got some people thinking intelligently about a lot of these important things that we discussed. And the book again, I haven't really said the title of it too much as I've been interviewing you, Joel, but it's called “The Immunity Code,” “The Immunity Code: The New Paradigm for Real Health and Radical Anti-Aging.”
I guarantee, you get this book, it's going to blow your mind. There's a lot in here, but I think it's one of the more valuable books you can add to your library if you really want to hack your diet, and your exercise protocol, your sleep protocol, your longevity protocol to the T. And so, I can't recommend this book highly enough. We'll put links in the shownotes for you to be able to get the book, as well as to all the other resources and shownotes that are going to be really comprehensive based around everything that Joel and I discussed.
Joel, dude, thank you so much for writing this book and for laying all this out for us. I should probably give you a pee break at some point.
Joel: Oh, thank you, man. This has been one of the funniest convos I think I've ever had. I mean, I don't get to nerd up like this very often and you're one of the few guys I can do this with. So, this has just been an absolute blast. Thank you for having me on.
Ben: Yeah. For sure, man. We'll have to go for farm shop round number two when I'm in L.A. I'll be coming to L.A. this July. So, I'll ping you and we'll make it happen. But in the meantime, folks, again, Part 1 at BenGreenfieldFitness.com/joelgreene with an “E,” Part 2, BenGreenfieldFitness.com/joelgreene2. Thanks for listening in and until next time. I'm Ben Greenfield along with Joel, the author of this new book, “The Immunity Code,” signing out from BenGreenfieldFitness.com. Have an amazing week.
Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at BenGreenfieldFitness.com, along with plenty of other goodies from me, including the highly helpful “Ben Recommends” page, which is a list of pretty much everything that I've ever recommended for hormone, sleep, digestion, fat loss, performance, and plenty more. Please, also, know that all the links, all the promo codes, that I mentioned during this and every episode, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.
It's time for Part 2 of my monster podcast with Joel Greene. If you missed part 1—in which we discuss rebooting your gut and sparking fat loss using some very unique biohacks and strategies—you can click here to listen to it now. Also, check out Joel's recent guest post on my blog entitled “Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity.“
So who is Joel Greene, exactly?
To put it simply, he's a man who had his 10,000 hours in before I was even born.
- In the 1970s, he was interval training.
- In 1979, he was doing Olympic lifts 3 hours every night.
- In the 80s, he began studying MCTs.
- In 1990, he began studying the keto diet.
- In the early 90s, he was doing what would be called intermittent fasting today.
- In the mid 90s, he experienced the rebound from chronic starvation. You read this today for this reason.
- In the late 90s, he went through his clean eating phase, his macro phase, and his ancestral diet phase.
- By 2001, he had his first nutrition website publishing cutting edge research.
- By 2006, he came to the end of all the above and discovered none of it worked over time and under real-life pressure.
- In 2007, he authored the first article to the health and fitness community based on the new science linking gut bacteria and obesity.
- In 2008, his website comhit #2 on Google for weight loss—with over 1,000 original groundbreaking articles that today represent many of the most widely copied ideas in nutrition.
- In 2009, he launched the world's first diet system based on targeting gut bacteria.
- In 2010, he was implementing signal activation of the AMPK pathway. The gurus only began speaking to AMPK in 2017.
- By 2013, he had the world's largest body of anecdotal outcomes for body composition targeting the gut bacteria.
- In 2013, he published the first article to the health and fitness community on the dangers of MCT oil supplementation.
Today, at 53, on 1 workout a week, eating whatever, whenever, with no drugs, SARMS, prohormones, or ergogenic aids ever, he is the world leader in hacking the body. He is the real deal. He has done it longer and always been far ahead. He looks it, he lives it. What the gurus say is impossible, he was living every day before they were gurus.
He has hacked peak human…
Working out once per week…
Eating whatever, whenever…
…and does it all on fast food!
He is the future of real-world health and nutrition, today.
Joel is the creator of the VEEP Nutrition System, the world's first commercially available program based on targeting gut communities to effect biomarkers. He is a featured author, speaker, and guest in top tier publications like Muscle and Fitness, 24 Hour Fitness Digital Magazine, CBS Online, Superhuman Radio, and beyond. His system has also been featured on the Dr. Phil Show, where it has delivered astounding life-changing results.
He is the future of real-world health and nutrition—today, and his new book was one of the most nitty-gritty deep dives into “rebooting your body” that I've ever read. The Immunity Code is simply a new paradigm and an entirely new way to think about caring for your body. The new goal is learning to control immunity, health, and aging using new science-based techniques (or hacks, if you will), to steer immunity for health, and to slow or even reverse aging.
This book will change everything you know about your body. Starting with simple, easy to-dos that build one on top of the other, you will emerge with a powerful understanding of how your body really works and how to control it over time, in the real world. Simply put, you will jump 10 years ahead of anything else on the shelf today.
During this discussion, you'll discover:
-Refilling fat cells vs. reshaping the extracellular matrix (ECM)…6:35
- Reshaping the ECM is preferable; refilling the fat is more common
- Post-fat loss biome intervention (4-8 weeks at conclusion of the fat loss period)
- End of the fat loss period is best to set the body toward the lean phenotype
- Similar to rehabbing an injury
- Reset leptin with high protein in the morning
- Get bioavailable collagen(use code BGF to get a 20% discount)
- Leptin interventions: high-calorie intake short-circuits leptin shortage
- Molecular hydrogencan enhance intramuscular fat production (use code GREENFIELD for a 10% discount)
-How hypoxia-inducible factor (HIF-1) and breathwork affect our sleep…15:15
- Two things necessary for energy production in the body: substrate (fuel) and oxygen
- Backup mechanisms for substrate (i.e. you have no food): liver and muscle glycogen, body fat, etc.
- HIF-1 is the backup mechanism for oxygen
- Cyclic hypoxia (insufficient oxygen) occurs most often during sleep
- Warburg metabolismhas a unique chemical signature
- Immune cells do well in a low oxygen environment (macrophages)
- If too many, the chemical signature is the same as that of cancer
- HIF-1 stabilizes in the cells, and activates oncogenic (cancerous) genes
- Metabolism of immune cells is paramount in an immunity-centric paradigm
- How to mitigate the effects of HIF-1:
-How to mitigate pexophagy…25:30
- Pexaphogy: selective autophagy of peroxisomes
- Paradigm shift in thinking regarding mitochondria: coequals with peroxisomes
- Membrane of peroxisomes stiffens with age; proteins don't pass as smoothly
- Resulting in imbalance among free radicals in the cells
- Strategies to mitigate pexophagy:
-Circaseptan vs. circadian rhythms…35:05
- Chrono-immunology: certain days of the week have unique nutritional requirements
- 7-day rhythm
- Sodium retention works on a circaseptan rhythm independent of sodium intake
- Cortisol levels peak on Mondays
- Cardiac rhythms reach peak on Wednesdays
- Seasonal biological needs
-Why NAD supplementation accelerates aging…39:50
- Immune cells and immune cell signals drive the aging process by accelerating the inflammasome
- Before taking NAD, watch inflammatory markers
- NAD makes inflammation worse
-How to keep muscles young…43:30
- Massage post-workout: deep tissue and stimulate blood flow
- Muscle growth, young muscle, and blood flow are synonymous
- Book: Becoming a Supple Leopardby Kelly Starrett
-The “daisy cutter” diet protocol…46:00
- Flood the gut with hemicellulose and cellulose (found in green beans)
- Lots of protein and no fat
- Don't do it too often
-The molecule that may make the keto diet impractical…47:30
- Keto diet increases oxidative stress short-term
- 4HNE electrophile: the mechanism that mediates oxidative stress
- Is produced in high amounts with alcohol consumption and fried foods
- 4HNE in high amounts with long-term keto diet
-And much more!
Resources from this episode:
– Joel Greene:
– Podcasts and articles:
- Joel Greene Podcast Part 1: How To Reboot The Gut, Eat Cheesecake Without Gaining Weight, Amplify Any Fasting Protocol & Maximize Fat Loss.
- With Tyler Lebaron about hydrogen-enriched water
- With Robert Slovak about Hydrogen waterand about Deuterium depleted water.
- The Ultimate Breathwork Ninja Guide: How To Banish Stress & Kiss High Cortisol Goodbye
- Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity.
– Book: Becoming a Supple Leopard by Kelly Starrett
- Bioavailable collagen(use code BGF to get a 20% discount)
- Exogenous ketones(use code BGF to get a 20% discount)
- Omega 3
- Omega 9
– Molecular hydrogen (use code GREENFIELD for a 10% discount)
- Biology of the Extracellular Matrix: An Overview
- Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance
- Pexaphogy: selective autophagy of peroxisomes
- Resistant Starches
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