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The Melanie Avalon Biohacking Podcast Episode #88 - Joel Greene (Part 2)

Joel is the creator of The VEEP Nutrition System, the world's first commercially available program based on targeting gut communities to affect health and body composition. His system has been used by some of the nation's largest employers, including major cities and hospitals and featured on Dr. Phil Show storylines. Joel is also a featured author, speaker, and consultant for nutrition companies, top tier publications, and major podcasts. Beginning with the first article on the gut biome revolution to the health and fitness community written in 2007 he has amassed the largest known body of outcomes targeting the gut biome. He is the author of The Immunity Code: The New Paradigm for Real Health and Radical Anti-Aging.
Joel has devoted over 50 years to the pursuit of health, nutrition and anti-aging. He was training intervals in the 1970's, taking MCT's in the late 80's, Keto in the early 90's and targeting AMPK by 2009. At age 55 he is a 100 percent natural athlete and uses no ergogenic aids while working out on average once per week and eating whatever whenever.
Joel has built two previous multi-million dollar companies in the tech space and been an entrepreneur for over 30 years. His own experiences building a startup with 15 hour days and non stop pressures led him to see that 99% of the popular advice does not translate into real world circumstances. He has devoted over 15 years to solving the problem of finding how to control the body under real life pressures.


instagram - @realjoelgreene


2:15 - IF Biohackers: Intermittent Fasting + Real Foods + Life: Join Melanie's Facebook Group For A Weekly Episode GIVEAWAY, And To Discuss And Learn About All Things Biohacking! All Conversations Welcome!

2:45 - FOOD SENSE GUIDEGet Melanie's App To Tackle Your Food Sensitivities! Food Sense Includes A Searchable Catalogue of 300+ Foods, Revealing Their Gluten, FODMAP, Lectin, histamine, Amine, glutamate, oxalate, salicylate, sulfite, and thiol Status. Food Sense Also Includes Compound Overviews, reactions To Look For, lists of foods high and low in them, the ability to create your own personal lists, And More!

3:15 - BEAUTYCOUNTER: Non-Toxic Beauty Products Tested For Heavy Metals, Which Support Skin Health And Look Amazing! Shop At Beautycounter.Com/MelanieAvalon For Something Magical! For Exclusive Offers And Discounts, And More On The Science Of Skincare, Get On Melanie's Private Beautycounter Email List At MelanieAvalon.Com/CleanBeauty! Find Your Perfect Beautycounter Products With Melanie's Quiz: Melanieavalon.Com/Beautycounterquiz

Join Melanie's Facebook Group Clean Beauty And Safe Skincare With Melanie Avalon To Discuss And Learn About All The Things Clean Beauty, Beautycounter And Safe Skincare!

4:55 - Follow Melanie On Instagram To See The Latest Moments, Products, And #AllTheThings! @MelanieAvalon

The Immunity Code: The New Paradigm for Immune Centric Health and Radical Anti-Aging. (Joel Greene)

5:40 - Potential problems with Keto and 4HNE

7:25 - 4HNE

9:10 - Bad Fats

10:25 - MCTs and fatty liver

11:50 - Omega 3s

The Melanie Avalon Biohacking Podcast Episode #61 - Dr. Cate Shanahan

15:45 - Inflammatory Pathways

21:30 - body fat

23:25 - damaged mitochondria cascade

The Melanie Avalon Biohacking Podcast Episode #60 - Wim Hof

28:05 - Inflamed Fat and Obesity

30:00 - Warburg Effect

The Melanie Avalon Biohacking Podcast Episode #74 - Benjamin Bikman, Ph.D.

The Melanie Avalon Biohacking Podcast Episode #66 - James Nestor

32:55 - DRY FARM WINES: Low Sugar, Low Alcohol, Toxin-Free, Mold- Free, Pesticide-Free , Hang-Over Free Natural Wine! Use The Link DryFarmWines.Com/Melanieavalon To Get A Bottle For A Penny!

34:50 - damaged cells during fat loss

37:15 - physical forces program cells

40:40 - White Fat and Brown Fat

45:05 - Collagen Fibers

46:40 - vinculin Antibodies and IBS

48:50 - Secretome

50:05 - Difficulty losing Fat as we age

51:55 - body set point

53:25 - restructuring ECM Practically

57:40 - How to keep body fat off

59:20 - Hacking FGF21 

1:01:25 -  LMNT: For Fasting Or Low-Carb Diets Electrolytes Are Key For Relieving Hunger, Cramps, Headaches, Tiredness, And Dizziness. With No Sugar, Artificial Ingredients, Coloring, And Only 2 Grams Of Carbs Per Packet, Try LMNT For Complete And Total Hydration. For A Limited Time Go To drinklmnt.com/melanieavalon To Get A Sample Pack For Only The Price Of Shipping!

1:04:00 - conflicting information and hacks

1:05:10 - the link of appearance to health

1:08:25 - Moving Every Day

1:11:35 - Old Blood and Old Muscle

1:14:10 - Massage

1:15:00 - EPO

1:17:05 - Vibration Plates

1:17:30 - AMPK, Sirtuins, NAD and CD38

1:19:25 - Supplementing NAD and NR

1:23:15 - The reality of how things work and getting what you really want

1:27:00 - Spot Burning Fat

Immune Centric Fat Loss Course


Joel Greene: It's incredible. While we're still in the low-carb world side of things. You talk about in the book the potential problems with, I think it was a low-carb diets and something called 4-HNE. Would you like to talk a little bit about that? I have other questions about as well, but--

Melanie Avalon: All this is under the aegis of one thing. It's that sustained high fat feeding probably breaks the mitochondria over time. There's very good reasons for this. In my book, I tackled an aspect of that, that was something most people can probably get their arms around, or at least generate a lot of interest in. You're going to retain a lot more if it's personal to you. I used to keto diets as an example. There is a byproduct called an electrophile. There's a byproduct of pushing certain types of fats, or pushing fats through the mitochondria. It's called 4-HNE, 4-Hydroxynonenal. 4-HNE is what's called an electrophile. It is an oxidized phospholipid. It's a highly, highly reactive molecule. It has a bunch of different side chains, and they can react in different ways. It seems to interact with the protein that the mitochondria needs to be bendable into form these little globules with, cardiolipin. It seems to basically break that and in turn breaks the mitochondria. You have too much of it.

In my book, I present this idea called Biological Duality. it's the idea that most things work both ways. If you want to understand how they work both ways, number one, you’ve got to track them over time. Then you've got to look at the other things like how much and what amounts and different things to understand how they're going to work. The relatable analogy is water. The right amount of water every day promotes life, too much water, too fast will kill you. It's the same with everything.

4-HNE is something that you see at the start of high-fat feeding or particular keto diets, and you'll see increased production of 4-HNE. It's highly beneficial in the short term, so you get an upregulation of glutathione within the mitochondria and it confers a benefit, and it's cytoprotective. Then what happens over time, though, is it can accumulate. As 4-HNE begins to accumulate, then you start to see sort of a range of effects in different types of cells. It seems to have opposing effects in cancer cells versus non-cancer cells. In certain types of cancer cells, it seems to kill them, which is great. You can probably explain some percentage of why the keto diet works on cancer by explaining 4-HNE.

Then the other side of that is that in non-cancer cells, in low amounts and non-cancer cells for short durations, it's probably highly beneficial. In sustained amounts over time, or just in increased amounts sustained over time in non-cancer cells, it could even promote cancer onset because certain types of cells seem to be able to push it next door, like cancer cells can push 4-HNE next door to the next adjacent cell, and then you can see cancer onset from that. But really the takeaway with 4-HNE is again coming back to what are the mechanisms? How do things really work? When we look at diets, the question that pops up a lot is you have these hyperpolarized camps of, “My diet’s better than yours,” or, “My macronutrients better than yours.” For every one of those, we can find mechanisms, whenever you see sort of imbalanced macros, not imbalance macros, but in balanced diet protocols. You begin to see mechanisms that when sustained long term are probably not so good.

The latest one that's making the rounds is-- I just went on Ben's podcast is this idea that certain types of fats are going to drive obesity, because they generate reactive oxygen species into mitochondria. You can call that a subset of high-fat feeding, really, in general, and that sustained high fat beating can break the mitochondria. It's not the reductionistic awe, the cause. Yes, this is the reason.

Melanie Avalon: Are these PUFAs that you're talking about?

Joel Greene: Yes. There's a theory right now I'll probably deal with this. My friend Ron, again, the founder of Quest sent me an article several months ago about a theory of obesity, this is the reason why obesity is what it is, and wanted my opinion on it. My opinion was basically that it's reductionism, again, it's just baby talk because I could focus in on any one of a number of mechanisms and make a very compelling case, as to this particular mechanism being the reason the central cause for obesity. At the end of the day, I would be forming what's called a gestalt. A gestalt is a [unintelligible [01:19:59] relationship where I take something, and I push it right in front of your face and get you to focus on it. I take the other thing and push it in the background, so you're not focused on it. Then basically, because it's all you're focused on, you'll think it's true, but it doesn't create reality. Reality is that multiple things drive obesity, and they all work together. That's that whole thing.

Melanie Avalon: So complicated. Also, within the fat world, so what are your thoughts on MCTs? Do they also have the same effect with 4-HNE? Do they tax the mitochondria? Do they tax the liver? I tend to go a little bit high sometimes on CA MCTs. I think about them a lot.

Joel Greene: Yeah, so it depends on where you're getting them from and it depends on how much and how long you're doing them. One of the things that we probably need to think about is things that are derived from coconut oil and downstream derivatives that are palmitate, palmitic acid. There's some pretty good research on high-fat feeding, driving palmitic acid palmitate, and then that in turn driving insulin resistance. From that, there's also some research on MCT striving fatty liver. I would say again, the answer becomes like protocols and balance. They're probably really good short term for different things. Every now and then I'll use them during my amplified fast days, along with like ketones. Every now and then, not all the time, but every now and then. They're probably a pretty good tool to do different things. They have a lot of benefits. It's just like anything else, I wouldn't live on them.

Melanie Avalon: When they're driving fatty liver, is that in the context of low-carb or in the context of carbs?

Joel Greene: Yeah, that's a really good question. I don't know that I would know the answer to that one. Actually, I probably have to give that some thought.

Melanie Avalon: These are the type of things I think. Omega-3s, speaking of PUFAs. One of the fascinating things to talk about in the book is the what, when, and how of omega-3s and its concept of taking them during the fast. In general, what are your thoughts on the omegas, the polyunsaturated fatty acids? Speaking to this, I did recently have Dr. Cate Shanahan on the show, and she wrote Fatburn Fix, which is very anti-polyunsaturated fats. I've been on the anti-polyunsaturated fat camp a little bit recently, especially like seed oils and things like that.

Joel Greene: Summarize for me really quick as I haven't listened to her thing, what's her take?

Melanie Avalon: Her take is basically that refined seed oils, PUFAs, as far as like when we were told to go low-fat in the 1970s, like our fat content didn't really change. What changed was the type of fats and it was switched to seed oils and omega-6s primarily. You touched on it already, but that the way they're processed in the mitochondria is inflammatory and is probably the root cause behind all the problems that we're having today with diabetes, the obesity epidemic. I've also been in the Ray Peat camp, I don't consider myself any camp, but I explore the forums and the world of Ray Peat if you're familiar with his work, his thoughts. He's all for PUFA depletion. I'm not taking on barely any PUFAs. So, omega-3s, omega-6s PUFAs. I know that's reductionist, but what are your thoughts?

Joel Greene: Yeah, it's actually a really good question. The nutrition collective conscious is going through like this sort of like a butterfly. Like the caterpillar bursting out of its little thing and becoming a butterfly.

Melanie Avalon: Wait, can I share really quick a mind-blowing fact that you might already know? I just have to. Did you know that the butterfly is not the caterpillar? The caterpillar does not become the butterfly, the caterpillar dies, and the butterfly is a different genetic route. Did you know this? It blew my mind. They think that what happened, like evolutionarily was these two animals made it or something and it just maintained two sets of DNA and so one starts, and then when it dies, the other one gets activated.

Joel Greene: That is fascinating.

Melanie Avalon: It's not a transformation. It's a death. Like a literal death.

Joel Greene: That is fascinating.

Melanie Avalon: I [unintelligible [01:24:07]. Sorry.

Joel Greene: Hmm. I didn't know that. We're going to get off this call today and I'm going to be like, “Okay, butterflies.”

Melanie Avalon: I know. We never going to look at one the same way.

Joel Greene: Wow. That's pretty fascinating, actually. In the bloom or the burgeoning of the collective consciousness and knowledge of things, what you're seeing over time is different ideas come into the foreground again come back to the idea of gestalt and we can come back and looking at, “Oh, wow, this is the thing,” but then new knowledge comes along, that rounds things out, and then we're like, “Oh, no, it's not the thing.” It's this crowd running from one thing to another, going, “This is the thing.” “No, no, that's not the thing, this is the thing.” Lately, it seems that there's this anti-PUFA crowd that's running around and doing its thing.

If we start with the idea that balances health, imbalances disease, just start with that. Also, with the idea that things can work both ways, they can be good, they can be bad. Well, this is going to take us is to like a more correct understanding of these things. Also, the idea that whenever we hear reductionism, it's probably wrong. Whenever you hear, “Ah, this is the one thing,” it's just probably wrong. In fact, I think I'll do it here, towards the end, I'll just make an argument, that's a completely different argument. it's equally compelling any of this stuff, and you won't even be thinking about the other thing, and the truth will be that they both have validity to them. It's just that the answer is that there's a lot of factors involved. That's the answer.

The thing with PUFAs is that they are essential, they are absolutely essential. When you study inflammatory pathways, when you study how inflammation works, and how it gets resolved, we have to have these things in the diet, we have to have some sort of imbalance, and there's good reasons for that. We really do need a balance. Something I did once is I broke down the lipoxygenase pathway on the omega-3 side of things, and I broke it down. I actually just for someone I was showing them because this person I was talking to was really into the omega-3s are bad, omega-6s are good thing. I broke down the pathway of showing that, okay, so you have all these downstream mediators of omega-3s, you have the eicosanoids, and then from there, you get resolvins, lipoxins, protectins, you have all these mediators that are necessary to resolve inflammation, and there's no getting away from chemistry, you got to have these things.

When we look at like these things, and the role they play with things like cancer, and with things like brown fat, you can't get away from them because these PUFAs, they work on things like PPAR gamma, and they work on things like PPAR gamma in the right tissues, and they do things that are very health-promoting, very life promoting. That being said, they can oxidize. We can make a very good case that non-enzymatic lipid peroxidation is one of the primary mediators of aging. We see damaged the inner mitochondrial membrane, damaged to the cell wall that could be mediated through lipid peroxidation. You can make a case that, well, the oxidation of fats is a primary thing that is creating damage to these very important membranes. That's a true thing. However, the body has mechanisms in place to deal with these things. The body has reductive mechanisms that have to be accounted for if you're going to make like a decent argument here.

In my book, I make this case that there's this-- when we look at super long-lived people, couple things going on. They seem to have higher levels of serum-like omega fats, and they seem to neutralize oxidation of those fats. Whereas people who are just sort of average lifespan, they don't have that, they're not offsetting the lipid peroxidation in the serum and all that from these fats. It's like the motor oil and the piston. You the piston, but you also need the motor oil. The motor oil is what protects the car from wear and tear. These omega fats have the potential to oxidize very specific key membranes, but then there are other elements involved to buffer the oxidation of these things, rather lipid peroxidation.

A good example of the power of omega-threes is with fat brown. When it comes to fat browning, there's some very interesting research you can look at that these PUFAs potentiate fat browning, and they could be used very strategically to get white fat to convert to brown, and they probably work synergistically with other things, like cold. We begin to come up-- I'm working towards a protocol here. We begin to look at these n-3 PUFAs, and what they potentiate, when and how and all that stuff. It seems like there's a really good home for them, probably when we're on an amplified fast or a fasting day, and then we're going to offset some of the potential oxidation with things like some red phenols at the same time, and then we're going to time them strategically to being cold. You begin to see where I'm going with this, they're neither good nor bad. I'm just working towards using them strategically, and I'm offsetting and mitigating the negative aspects potentially that are there.

What you'll hear a lot of is sort of these newer arguments that they're the cause of all evil. That's just really not true. It's just not accurate. I can make a case, let me do this now. I'm going to not refute those arguments, but I'm going to do a just stall, I'm going to take the PUFAs are bad, and put the background or put something else in the foreground, and you're going to forget about PUFAs by the time I'm done. You're going to think, “Oh, my gosh, this is the thing.” Then I'm going to pull that back and I'm going to show you how they both contribute.

When we look at obesity, and we see that inflamed fat is a big deal, but that seems to be an issue with obesity. It seems to be what's driving obesity. We go, “What's inflaming fat?”

There's a very interesting thing that happens when the gut is compromised, you're going to get an excess of lipopolysaccharide into your fat tissue. It's called tissue translocation. Lipopolysaccharide, in the presence of your adipose mass, will create what's called-- you're going to get macrophages concentrated in your fat that are inflammatory by their very nature. A macrophage is the first line of defense in the immune system. They're the first strike team, the first one to get in there. There's different kinds of macrophages, but for simplicity's sake, there's the inflammatory killers and then there's the healers. In my book I call the killers, the red team, the healers, the blue team. You see something very interesting. In the presence of lipopolysaccharide, there is an NAD salvage pathway that gets amplified. What you see is that NAD phosphoribosyltransferase, which is an enzyme necessary to salvage NAD, gets hyper-activated in macrophages. Then what it does is, it causes clustering of macrophages in your body fat.

Then what that does is you get this inflammatory cascade, mediated by macrophage, populations in your body fat, all caused by lipopolysaccharide translocating from the gut into your fat. Now what you have is this inflammatory issue in your fat, that supplemental NAD will feed. It’ll feed the fire of this because you've got these populations of macrophages that depend on NAD saturating your fat that are putting out these inflammatory signals. The thing about body fat is that it's a reservoir of very specific types of cells that concentrates senescent cells. What happens is, you'll see this magnification of senescence cells in your body fat, and then your body fat acts like this inflammatory megaphone. This will cause all these sort of downstream issues that will cause changes in the ECM. It'll cause specific proteins, specific collagens to be deposited in the ECM that stiffen the ECM. We haven't even gotten to body fat. We're going to spend a good chunk of time on this here because it's so critical.

What you see here is that basically from this little thing, tissue translocation of lipopolysaccharide, we see imbalances of immune cells in body fat that inflames your fat mass. Are you thinking about PUFAs right now?

Melanie Avalon: I'm not. Oh, my goodness. It worked. I was like, “I'm still going to be thinking about them.” Oh. [laughs]

Joel Greene: What I just did is gestalt.

Melanie Avalon: It's like a magic trick.

Joel Greene: Well, that's exactly what's going on. Magicians know something, they know that if they can control your focus, then they control how you think. By controlling your focus and getting you focused on something else, it's entirely true. I've controlled your mind by getting you to think this is the one thing, but the reality is both of these things matter. Isn't just both of these things, there's other things in the picture. What this takes us back to is when I started the program with, how things really work. I'll tell you how they don't work. They usually don't work reductionistically. they usually don't work that way. When you hear these reductionistic arguments, you can probably be pretty certain that it's not all the picture. What I just did here was took us from forgetting about PUFAs to entirely focus on LPS and tissue translocation of macrophages and NAD salvaging macrophages, now I'm just bringing it back into life. Actually, there's truth to both. You can oxidize lipids, those can damage the mitochondria, that can have an issue, but also you can-- do you see where this is going? Do you see what's happening here?

Melanie Avalon: For example, so say that we get damaged mitochondria from-- I've never heard of called PUFAs, but PUFAs, whatever they are. Could that also beckon for macrophages and continue that whole cascade?

Joel Greene: Depends on the tissue that we're talking about here. If we're talking about body fat, then that's a whole discussion. That's its own thing.

Melanie Avalon: For listeners, because that was a lot. Do you mind if I recap what you just said, and you can tell me if I heard it right, then I might define some terminology for listeners along the way, especially if we dive into body fat, just so they have a good idea of what these words mean? Lipopolysaccharide, like I said, the bane of my existence, which is created from gut bacteria, and it's registered as a massive toxin by the body so it often creates an inflammatory response. Although side note, are you familiar with Wim Hof? We're talking about cold things?

Joel Greene: Mm-hmm.

Melanie Avalon: I recently had him on the show.

Joel Greene: Oh, wow.

Melanie Avalon: I know. It was like the most motivating conversation I've ever had. He's so inspirational. I am obsessed with the cold though. That's a whole tangent.

Joel Greene: Sure. It's part of the body fat thing. We'll bring it into that too.

Melanie Avalon: Oh, perfect. One of my favorite things from his work is the studies they've done on like injecting people with lipopolysaccharide. Then them doing his breathwork. I don't know if it was paired with cold, but basically it modulated like IL-6, IL-8, IL-10 immune response so that it was less inflammatory, which made me so excited because I think I walk around in fear of LPS. In any case, so LPS from gut bacteria translocating across the gut, ending up in our fat stores, creating an inflammatory situation because like I said, the body registers it as severe toxin recruits, the body sends out these macrophages, which are these cells that basically-- I think it means like eater or something, and they go and they eat trying to get rid of the invader, or whatever it may be, but in the process creates a lot of inflammation because anytime there's a war, there's going to be an inflammatory response.

Then, you were saying that, and this is a mindset shift, but that NAD, which I've talked about a lot in this show, and I've had a lot of episodes about, which is a key player in our hope, and normally I see it as a good thing, but you're saying when there's excess NAD in the situation, the macrophages, which are trying to clean up the situation, but are inflammatory that they're using this excess energy, so it's just perpetuating more and more inflammation. Is that sort of?

Joel Greene: Yeah, very good. Actually, really, really well done. It just takes us back to, it could be good, it could be bad. If your listener listen this, part of your brain wants to give up and go, “I give up, I don't know anything.” I encourage you to not do that because the way that I learned all this stuff was just in baby steps, like, I couldn't understand all these big words all at once, but I could understand one stupid little simple thing, I just started with that and then I just learned one more little thing. By just learning one more little thing, you can become quite formidable, much, much faster than you think. We're in a different era now. The way we learned has been decoupled from physical locations, like colleges, and schools and people. You can learn at an exponential rate if you choose to. It's an amazing time if you're curious, and if you like to learn, because you can learn at such an accelerated rate, that it's never been possible before in human history. Don't get intimidated. It's taken me a long, long, long, long, long time to just put all these things together.

The truth is that some things in life ask a lot more of you. When it comes to getting more out of your years, getting the most valuable thing possible, more time, it's not McKnowledge, it's not a happy meal, it asks more of you. It's sad to say it's not for the many, because in many cases don't want to learn the how, they don't want to learn this, it's students too much. I think if you're listening to this, you do, and it's for you. So, just be patient, and you'll pick it all up, you will. It just takes exposure multiple times.

Melanie Avalon: That was one reason I loved your books so much, because it's such a wealth of knowledge all within these pages. I read it so slow, like, I read like a little bit every single night because it was just so much to take in, but it was really, really, really incredible. Listeners definitely get the book, there's just so much in there.

Joel Greene: There's this counterintuitive thing that happens when in the case of inflamed fat, particularly obesity, we see these imbalances of specific types of immune cells, particularly macrophages. There are certain things that these macrophages do. They carry with them a cargo, that cargo is a chemical signature. A different way to look at disease is to look at the cargo carried by these macrophages. In terms of its chemical signature. The chemical signature is high oxygen output, high sugar utilization, high free-radical output. Okay, those three things. A funny thing happens, wherever that cargo goes, it spreads. It stays there too long. Then if it stays in any tissue too long, and there's too much of it, high oxygen output, high sugar utilization, high free-radical output, a funny thing happens. It's called cancer.

Macrophages and immune mechanisms and body fat are all central to this going on. The way that we can understand, a more nuanced and better understanding is that when the body is super inflamed, or you're fat super inflamed, or you're getting older, and you have a lot of senescence cells, that these macrophages are feeding on NAD, and they're upregulating in a key enzyme that it takes to salvage NAD. When NAD is introduced, it's actually feeding them and it's feeding the inflammatory process. Now, the converse of that is we need supplemental NAD as we get older, but what we have to do is follow an order of operations to first clear senescent cells, spin down macrophages and then take in the NAD. Again, this takes us back to what, when, and how, and how things really work. Just wanted to get that out there. Well, okay, let's talk body fat.

Melanie Avalon: I have a quick question really quickly, though, about the high oxygen, high sugar, then the cancer cells and things like that. Is that related to the Warburg Effect?

Joel Greene: Yes. You see Warburg metabolism in macrophage, but you see it in other cells way before you see it in cancer. I left this out of my book because I thought it would be too much for the reader. But I've done some trainings recently for some professionals and stuff on this. I'm bringing the extra goodies now. I call this DEFCON 1. DEFCON 1 is a Cold War term meaning launch the nukes, take cover. The way to think of it is this, the macrophages are the intercontinental ballistic missiles, and their cargo is DEFCON 1. DEFCON 1 is their chemical signature, they carry it to tissues, and if they're there too long, other cells pick it up. When cells pick up DEFCON 1 too much, then cancer is not far behind because you're seeing Warburg metabolism spread, you're seeing high oxygen output, high free-radical output into the environment, you see oxidative stress, you could make a good explanation for breast cancer this way and a lot of kinds of cancers. It's beginning to look at things apart from sort of the tissue or this or that and look at it in terms of the chemical payload.

Melanie Avalon: One more quick question because I was looking at the Warburg effect, because you mentioned it, and then it came up, I was reading last night Dr. Bikman’s book, and he's talking about insulin, but he was talking about it. He was saying so cells generate energy with glucose, not in the mitochondria. When that happens, where are they creating the energy?

Joel Greene: Well, first, you have glycolysis, what causes like your starter fuel, but it's not very efficient, you only get like 2 ATP molecules for it. It takes glycolysis to make pyruvate and then pyruvate gets pushed down the TCA cycle. Then from there, you're going to get 38 ATP, you get all this power from it. Under certain circumstances, OXPHOS gets cut off and you just have-- Well actually, this is critically important. Mostly under hypoxic circumstances, when the hypoxia-inducible factor one is present, you see a cessation of OXPHOS. What you see is TCA cycle gets cut off, and then you see this emphasis on Warburg metabolism. What you see is that when cells are oxygen-starved, you tend to find Warburg metabolism.

Melanie Avalon: Okay, this is so fascinating. Now I think of all these other tangents because I also recently had James Nestor on the podcast for a whole episode on breathing.

Joel Greene: Oh, I love James, we were in this meeting, back in 2017, Ron Penna put together a bunch of guys like us in a room at Quest. James and I were both writing our books at the same time and I got to know him then. Super great guy.

Melanie Avalon: Yeah, it was mind-blowing. His book as well was a game-changer for me, like just rethinking breath and all of it. That's one of the things he talks about-- I think one of the first things that he talked about in the book is powerful effects of breathing, oxygen, hypoxia, the whole relationship with that in our bodies, but rather than going on that tangent, where we're going to go into the body fat. Mind-blowing. Listeners, get ready. You talk about something that I have never heard talked about anywhere else ever. It is just so fascinating, and it has to do with when we lose fat, and the actual mechanical damage that occurs to our fat cells, and the implications of that for why we are often very likely to regain weight. Also, how yo-yo dieting just makes it harder and harder and harder. What is going on there?

Joel Greene: [laughs] What's happening? Yeah, what’s happening with the fat? It's absolutely crazy to think, but for over 70 years, we've had these prescriptions for dealing with body fat and not one was ever based on what's true about body fat. Not one was ever true about what really happens mechanistically when fat cells shrink. At the top of it when I say that people just think, like under some huckster trying to, blah, blah, blah. But by the time I get to the end of it, people like, “Oh, my gosh, why hasn't this been talked about?” To understand it, we have to first understand what body fat is. Most of us have been coached into thinking body fat is just fat. There's just nothing that could be less true than that. Body fat is an organ and at the highest level, it is an organ with multiple functions. It's an endocrine organ, it's a paracrine organ, it's an autocrine organ. It has a very vast influence over metabolic function. The best way to characterize what body fat is, and in order to understand this, you have to wipe away what you think it is, because by the time we're done, I can promise you, you're not going to believe what you used to believe.

The best way to characterize body fat is to say that it is a system and that system can have multiple configurations. Those configurations depend on the parts of the system. The parts of the system are things like collagen fibers, stem cells, immune cells, fat cells, very specific proteins called the adipocyte, secretome, and number of things. It's very much a complex system. I use the analogy in my book that body fat cells mothership and that mothership contains a lot of different kinds of cells in it. The configuration of the parts of the system exerts enormous power, not just over your weight, but even over how fast you age.

The first thing to understand is what actually happens when fat cells shrink. That's the first thing we have to start with. When we start this discussion, we have to begin with some new ideas. Those new ideas fall under immunology and they fall under what's called essentially mechanotransduction, or mechanobiology. It's this newer emerging, understanding that physical forces, program cells. That one of the ways that cells are programmed, is through the interpretation and dissemination of physical traction and stress forces across the cell. When we look at body fat, and we begin to look at like body fat structurally, the analogy I use in my book is a wall made from bricks and mortar, and the simple way to understand it is that the mortar is what's called the extracellular matrix or just the stuff around our fat. Then the bricks are the fat cells.

There's a simple analogy to understand the impact of shrinking fat cells. If your house was made of bricks, and we shrunk all the bricks, all of a sudden, all at once, the house might collapse. The reason the house will collapse is due to mechanical tension. You would have a transfer of mechanical force going from the system as a whole to just the mortar, and the mortar would be seriously damaged by that transition of mechanical force. When we begin to look at body fat, and we look at how it actually works, which again, that's all we're talking about here. Remember, that's where the power is, the power is in how things actually work. What really happens over time when you mess with how things actually work?

When we look at how body fat actually works, we see that there's these very interesting relationship between the extracellular matrix and fat cells themselves. It's mediated by what are called focal adhesions. Focal adhesion is a point. Think of a focal adhesion as like a shock absorber, or an engine mount. It's the point at which one thing connects to another. In that system, it's a multi-protein system that crosses the fat cell membrane and connects it to the extracellular matrix. What's really fascinating about this is it seems to have mechanisms in it that are designed to detect measure and pass on information about stress and portion stress and traction stress. In fact, there's even something that could be considered a portion bolt put into there. It's a protein called vinculin. What you'll see is that when you look at how body fat actually works in these focal adhesions, there are these specific proteins called beta-actin. Beta-actin has like a torsioning system called vinculin. Vinculin is a protein that essentially its solution is to work as a shock absorber or torsion bolt. What a torsion bolt does or torsioning system does, it works as a buffer between the mechanical forces acting from one surface to another and helps to take the shock.

What happens is information about physical-mechanical stress is translated from these torsion bolts or from these proteins down into the nucleus of the cell. Then in the nucleus of the fat cell, there's all these genes that control what are essentially mechanosensitive proteins. These are proteins that react to physical-mechanical stresses. To understand the importance of this, let's take the example of brown fat. I'm going to show for you here how brown fat or the utilization of brown fat for energy is 100% controlled by mechanical stress 100%. What you have in brown fat, or all fat is you have a cytoskeleton or a skeleton within the cell, it's invisible, but it's these 10 rolls and filaments that cross the cell. It's made out of what are called actomyosin fibers. These are the same fibers you find in muscle, but they work very differently in white fat.

In white fat, what we see is that you just store fat, there's no mitochondria for the most part. When we begin to apply certain things to white fat, like cold or omega-3s, what happens is white fat can begin to effectively become muscle, as crazy as that sounds. Here's how it works.

Within the actin cytoskeleton within fat, in response to stimuli, such as like let's say cold or certain types of maybe phytonutrients, what happens is, mechanical signals get passed into fat cells, get passed into brown fat. The act of cytoskeleton within the cell tenses up, just like muscle, and it needs something to power the tensioning. What it does is it makes more mitochondria because the way muscles work is when a muscle flexes, you're burning in the mitochondria. It takes energy to power those contractions. Within the cytoskeleton, within brown fat, you have essentially these actin-myosin fibers form that are essentially muscle. For all intents and purposes that works the same way. What power is that is more mitochondria. What powers the uncoupling process where fat can be burned and glucose can be burned in fat cells, in brown fat is tensioning. Just like muscle, these two cells tense up, they uncouple, and they burn energy. That's how important mechanical tension is to fat.

Now, in the case of white fat, and body fat, what happens is that when we shrink fat cells, we are essentially breaking away from the extracellular matrix. We're taking the focal adhesion points, the points that bind fat cells to the ECM, and we're inducing damage to those points. It's very interesting. There's newer research. In fact, I quoted in my book, some studies from Maastricht University. Well, there's been some follow-on studies now in 2020, that have shown what happens post-weight loss. Post-weight loss, what we see within, besides within white fat cells is that the metabolic functions within those cells go down. The immune functions within those cells shoot through the roof. What we see is that genes, immune centric genes, controlling things, controlling immune signals, like interferon-gamma, and interleukins skyrocket, and so the heat shock proteins, they skyrocket when we lose fat.

The reason, if you're going to mechanistically break down what's going on, is that the focal adhesion points when fat cells shrink, are being damaged, you're breaking away from the ECM. Then we need to repair those. Well, what is repair? A function up within the body. Repair is a function of the immune system. What we see post fat loss in the maintenance phase is all of these immune mechanisms kicking in. The purpose of these immune mechanisms is when fat cells shrink-- One thing I point out in my book is that the nucleus of fat cells is very different from most cells. In most cells, the nucleus sits in the center, so it's protected from damage by the cytoplasm. In fat cells, it sits on the edge, it sits right against the cell wall, so it's very easy to damage fat cells. When fat cells shrink, the fat goes away and they break away from the ECM, a couple of very important things need to happen. Number one, the ECM has to either remodel to fit the shrunken fat cell, or the fat cell has to refill the fat. One of those two things have to happen, there's no middle ground.

When we look at the cost to do either, it's much cheaper for the body to fill fat cells back up than it is to reshape the ECM. To reshape the ECM involves very specific enzymes like matrix metalloproteinase-11. These enzymes, they have both beneficial and not so good impact on the ECM and the cellular milieu. What happens is, when fat cells shrink, if we're going to shrink the ECM to match the smaller new fat cell, the first thing we have to do is we have to reattach the fat cell to the ECM. That's going to take very specific types of proteins, you have to pull the cell. In pulling the cell, you're stretching the cell, you're causing damage to the cell when you pull it. In order to fix the damage, you have to make [unintelligible [01:53:00] and things that refold proteins back. The relationship between the ECM and the fat cell is very two way. They work two intelligent computer systems that constantly make adoptions, the one to the other.

What will happen is mechanical tension forces from the ECM, go down into the nucleus of the cell, and they reprogram the cell to make fibers that are different. Collagen fibers that are very, very different from the ones that they're replacing. Those collagen fibers are loaded up in the ECM. We think of collagen fibers as just good things. Well, it's collagen, it must be good, right? Not necessarily the case. You can have very specific collagen fibers that work as inflammatory mediators. The best example is known as collagen 6A2-3. Collagen 6A2-3 is called endotrophin, you find a lot of it in obesity. It's the result of the ECM getting stressed from mechanical pressure. What we see when we shrink fat cells is this giant inflammatory response, or rather this giant immune response, because it's immune mechanisms that are coming into play to repair the damage.

In my book, the case that I make is that we have past the old paradigm. We've reached the limits, the upward limit of the old paradigm of just fitness as the explanatory power and we've moved into a new paradigm one that involves is immunology and whole-body health, because it's immune mechanisms that are governing the show and the money in the process of how things get healed when we shrink fat cells. The big takeaway here is that when we shrink fat cells, we're injuring them, you're injuring the fat cell when you shrink it. The injury process is governed by immunity, and its immune mechanisms that ultimately repair the fat cell. The long-term impact, which takes place in the weight maintenance phase is to upregulate all kinds of different genes that are related to immune signal cascades. That ultimately is what's going to determine if we can keep the weight off, our immune mechanisms. That's a very long-winded explanation. I hope you guys are still with me on that, but it's necessary to get out there and we can break it down from there.

Melanie Avalon: This is incredible. I have a really quick question. You mentioned vinculin. Is that the same thing they test for like vinculin antibodies for IBS? Have you heard of that? I don’t know, it was two years ago, or a year and a half ago-ish. There's this huge thing, because I was like, “Oh, we can finally do a literal test for IBS,” especially, I think if it was post infection.

Joel Greene: Yeah, probably just because the raw materials that we're using are not unique to fat cells. When you're looking at fat cells, you're looking at proteins like beta-actin, laminin, collagens, vinculin. You're looking at all these different things, and they're used in other parts of the body.

Melanie Avalon: Okay, yeah, because the idea was that people get food poisoning or something, and then their body-- I wonder if it was because then there was an increase in vinculin, and then the body makes antibodies, but then it's against the gut, I don't know. It was like a thing for a little bit. There was this IBS check, I think it was testing for that. It's really interesting. To recap all of that, so basically, if we look at our fat cells like brick and mortar, when we lose weight, it's like we're losing a brick, and mortar still there. We have two options. We can either bring back the brick, which would be [unintelligible [01:56:09] the way, or we can completely remodel a whole foundation of the house, change the mortar, so that it's-- is it changing it so that like smaller bricks?

Joel Greene: Yeah. Think of it this way, with the brick-and-mortar analogy, if your whole house was made of bricks and mortar, and then you shrunk the bricks, and by some miracle, the walls didn't all collapse, but you had all these stress fractures in the mortar from kicking all the way to the house. What you do is you would fill in the gaps. You'd fill in the gaps between the mortar and the bricks with more mortar so that now they fit the bricks, that's what you would do.

Melanie Avalon: There's little baby bricks now.

Joel Greene: Like new mortar. Yeah, you have smaller bricks, and you need to fill in the mortar now. Everything would shift around a little bit, but if you could do that, and you had a smart house that reacted dynamically, then that's what you would get. Now, the thing to understand here is, there's a lot of things at work with this. There are genetic differences with people. There are a number of things that play out in the weight maintenance phase. There's something called the secretome. Secretome is a family of dozens of proteins that are produced in response to fat loss, post fat loss, and has a lot to do with whether or not you're going to regain the weight. A lot of it also has to do with the presence of fibroblast growth factor 21, and fatty acid-binding protein four and matrix metalloproteinase-11, and all these different tools that we need.

The thing to understand is that there is probably an accumulative effect to doing this. You have to understand it from the perspective that there's an enormous inventory of baked in responses working against you, when fat cells shrink, because coming back to how words program our minds, we use the words, gut in my best shape ever, lost the weight, low body fat, we use all these words that are positive words, and we think we've solved the problem. Your body doesn't know what those words mean. All your body knows is the history stored across 1000 generations through all your ancestors, which is that typically when fat cells shrunk is because there was no food. We've got to do something about that, we got to make sure next time it happens that we don't get a skinny.

Now, what I see a lot of are people who come to me who can't get lean anymore, and they had no problem, when they were young, in the 20s and 30s, they got lean, and then it progressively got harder and harder and harder. There's these old-school explanations of slow metabolism and, thyroid and all this stuff. What's brand new that no one's ever considered is that there is a progressive stiffening or worsening of the ECM as a result of weight cycling, that is induced by all of the mechanisms that are at work against us when we lose weight. In my book, there's a page where I list on one side of the equation fat loss, and then all the other things that are against you. There's a lot of things that you got to overcome. You got to overcome the energy gap, which is you have lower metabolism, but then you have a lower leptin, which makes you want to eat more. You have alterations, and the body's feeding mechanisms that make you want to mix the case better. You have mechanistic, mechano-driven things, driven by the physical shrinking of fat cells. You have a lot of things that are against you when you lose fat that are-- that for the purposes of survival want to put the fat back on it.

When you put it in a historical context, where the only people that were ever fat were rich people, and that everybody else was skinny, that starts to make sense because everybody else was starving. Long term, what is brand new and just starting to bubble up is that the act of reducing body fat may provoke similar mechanisms that we see with obesity, very similar mechanisms and it has to do with the reshaping and the repeated reshaping of the extracellular matrix. Where this brings us to is, it brings us much closer to how things actually work. The closer we get to this, the more we can come up with a solution that truly brings us to much closer to one and done.

Melanie Avalon: Does this at all relate to this vague, nebulous idea of a body setpoint? Might it be a successful reshaping of the ECM, if people lowered their setpoint?

Joel Greene: No, not really, because we have this idea that it's in the cluster of those things. That would probably fall under the energy gap. The energy gap is this massive problem we have to overcome when we lose body fat. It's just that the body doesn't need as much energy as it used to, but you want to eat more. Getting the body to a place where you're not eating more and comfortable with the lowered metabolic output is under that umbrella. Let's say that's maybe a factor in the equation, but we're going sort of, in addition to it above and beyond that, when we start to really consider that, that this is an immune problem. We think of body fat as a metabolic issue, but really, when we look at the mechanisms governing weight regain, they're immune mechanisms. There are things like macrophages and things like heat shock proteins, and things like interleukin signals. In fibroblast FGF21, these are the things that are governing whether or not we're going to regain the weight. It takes us into a new way of looking at body fat. It takes us into an immune centric approach, and it changes how we do things, and it changes just about everything. I'm going to go out on a limb and say that is the future.

Melanie Avalon: I could foresee that happening. If we lose weight and we want to take the avenue of restructuring the ECM rather than refilling with fat, can that process occur without an inflammatory cascade? Or, do we just have to bite the bullet and there's an inflammatory cascade that we wade through?

Joel Greene: I believe it's definitely hackable. That takes us into a new avenue, it becomes that-- Yes, we can, and the solution is what we call hacking. At a high-level hacking represents two notions, it represents the idea of time, that time is a factor, and we have to take time into account because you can solve this problem, just go get paid to be fit, that'll solve the problem for you. One of the ways you can solve this problem is that if you implore an ancestral analogy. Ancestral analogies are not science, they're not fact, but they're useful. I use them but we always have to tell ourselves that, “Okay, I could be wrong here, but this makes sense to us,” is that post-starvation, post-feasting, you kept on hunting. We couldn't get any food, it was a bad winter, we were eating dirt and weeds and roots and whatever. Then the game came back, but we got a kill, we feasted, we slept. Then we had to go back out again, and we had to go hunting again, we had to burn a ton of energy. That worked as a counterbalance. The energy expenditure needed like post-feasting worked as a counterbalance to all of the other starvation-based mechanisms. We don't have that now, in the modern world we live in.

In the weight maintenance phase, or let's call it the post-feasting phase, we have some very, very considerable barriers. The most important being that the probability of time going to zero is 100% for extended periods, if you're in the real-world ecosystem, and you can't solve it with platitudes, like, “Well, you got to make the time. You got to walk the talk,” blah, blah, all that stuff. All that stuff is born of the fitness ecosystem. It's not born from the real world. You talk to anybody in the real world, it's a whole different animal. I mean, I have clients, I can tell you for a fact, that their week and their day is just keeping up. These are people who are fairly wealthy, fairly wealthy, too.

Imagine as you begin to go down income strata and you start to look at what really happens in the real world and you combine stress, you combine family issues, job issues, all these things, COVID stress, all this stuff, and competition for your time becomes this limiting factor mitigating what would in effect be hunting continues. The energy expenditure required for continued exercise non-stop. In lieu of that, we need hacks, we need a way to hack the system here, and it's a very real necessity. What we're looking at in this new scenario is that we begin fat loss and it's very, very different. We don't begin with fat, we begin in the gut. We begin with a gut because the gut and our body fat have a connection, and I've already illustrated that with macrophages and lipopolysaccharide, but it goes much deeper than that.

There's one school of thought that, well, there really isn't any bacteria common to lean people, it's conflicting, we can't really answer that. What I would say that is, really? Look at obese people and what do you see? When you inventory the research for obese people, what you consistently see is they're lacking bifidobacterial and Akkermansia, and when you give them those two bacteria, they get lean, like almost one to one in the research. There is a very strong connection between the bacteria in our gut and the ability to store fat or burn fat. In my book, I talk about fasting-induced adipose factor, which is a protein-related to the renin-angiotensin system, but it's potentiated by bifidobacteria. It affects lipoprotein lipase, and it affects fat storage. It's a direct connection between what's in our gut and our ability to lose or store fat. We begin in the gut and we begin by conditioning the gut and getting the gut into a place that mimics that of the leanest, healthiest people. That's sort of odd.

We think of body fat, okay, well, I'm going to go hop on the treadmill and I'm going to start dieting and I'm going to do all these things. But in a new immune centric approach, we're focusing on bacteria that promote immunity and promote the lean phenotype. That's a point where we disembark right away immediately upfront from the old way of thinking about things. Then, as we're looking at body fat, and how to get it down, and how to keep it off, we're incorporating a lot of things. We're incorporating not just one thing, but multiple things that impinge on different things. A good example would be brown fat, and fat browning and fat beiging and cold, and things that work synergistically with cold, like cayenne, for example, or things like cAMP activators, or things like omega-3s. We begin to come up with an order of operations, that really is throwing everything at the problem, but doing it with an immune centric approach to body fat.

The most important thing is, once the fat is off, it's far more important than getting the fat off. The thing with that is getting the fat off super, super hard for most people, like really hard. It's hard to get fat off. But much, much, much, much harder is getting the fat off in a way where it's not going to come back. In an immune centric approach, the most important phase of fat loss is after the fat is gone because that's when all of the different genes and proteins and signals and all that stuff kicks in and the weight maintenance phase that is going to dictate whether or not we can keep it off. This is something we have to hack. A good example is FGF21. FGF21 is a hormone, we make it in several places in the body. It's part of a family of proteins. Basically, they're all involved in one way or another in mitigation of stress, whether that's physical stress, mechanical stress. FGF21 is this hormone that we used to think was a fasting hormone because you see more of it when you fast. The newer research shows that it's actually you get more of it when you're obese too. It works a lot of different ways, but FGF21 is a good example of something we can hack post fat loss to mitigate weight regain.

Melanie Avalon: You talked about how it induces a futile cycle in our adipose tissue. Does that mean it just makes our fat tissue just burn calories, or what's happening with it?

Joel Greene: FGF21, fibroblast, I had the hardest time saying that word. Fibroblast growth factor 21, it's a tissue repair hormone, but it does a lot of different things. When we have a lot of it in the liver, it enhances fatty acid oxidation, but it does a lot of things. It can increase lifespan, energy expenditure, fat loss, fat browning, it can improve glucose uptake in the cells, it can sensitize insulin, it can influence the sweetness of sweets, so it can make post fat loss, it can make us eat more. Interestingly, high-fat diets actually induce FGF21 resistance. Like a keto diet long term, what you'll see is that the inflammatory state of your white fat mass improves, but the inflammatory state of the liver worsens, because what happens is you get more FGF21, but then you get FGF21 resistance, so it actually doesn't get uptaken in the liver.

FGF21 generally speaking, it maintains energy balance, and one of the ways that we can increase FGF21 is with cold, and it helps us with-- basically helps uncoupling and helps glucose uptake in the brown fat. It also does something which is really important. There are what are called sphingolipid ceramides, these are basically like adhesion points on macrophages that drive insulin resistance, and FGF21 helps with these. What's really important is post fat loss, and we need to get it up post fat loss and that's really the thing with it. There's a lot of different ways that we can do that. Acetoacetate seems to increase it, methionine restriction seems to increase it. There's a lot of different ways to work on getting FGF21 up and it really just comes back to what, when, and how. Is FGF21 good? Yes. In some cases, is it bad? Yeah, some cases. It's a what, when, how thing. Well, when do we need it? Well, we really, really need it post fat loss. If we can get FGF21 post fat loss, it's one of the keys to knocking out the response of the body to put weight back on. That's where all the hacking and all that comes in.

Melanie Avalon: You can read studies showing that, “Oh, spices boosts your metabolism,” but then there'll be another article saying, but you only burn like an extra 10 calories, it doesn't really do anything. If you're hacking literally everything that you're doing as far as what you're eating. You talk about a lot of different fascinating hacks and protocols in the book and I think that really adds up. It can change the overall signaling of everything, and it's just really, really amazing. The exercise world, your approach to that, talk about minimum investment, maximum results. What are your thoughts on exercise for those of us who, like you said, that's not our job, so exercise is not our career? How should we approach that and how can we potentially hack that?

Joel Greene: In my book, I make the case that paradigm shifts come when a new way of doing things comes from outside the accepted way of doing things, when we get a new lens. The lens that we've been under for over 60 years here, links appearance to help and it came out of bodybuilding. It came out, as if you trace the way we do things right now, and you put a bow on it and go, “Where did this come from?” The origin was really been getting bodybuilding mainstream and popularized in the 70s, beginning with Joe Weider, there was magazines in the 80s, and then Bill Phillips in the 90s, and then the advent of social media. All these things have been built on this one house. This one house is based on one sort of idea. It's the idea that it puts appearance in front of health, that’s how you look at the forefront. There's a very strong correlation between how you walk in your health. They correlate very strongly. There's also a very strong decoupling between appearance and health.

I personally know lots of people who have what you would consider an amazing appearance and are not in good health. Really what's needed is a shift in our ethos to begin to think of an immune-centric approach first, which is really going to drive health and you're going to look great, you're going to look fantastic, but it's not bodybuilding because bodybuilding for most people in the real world, sort of that, best shape ever all the time thing, it doesn't work in the real world ecosystem, because you don't get paid to be fit. A different way of looking at the thing is to, again, we’ll come back, then how do things really work?

Well, how things really work is that over time, your blood is going downhill, the quality of your blood’s going downhill. The viscosity of your blood, the way your blood circulates, the actual proteins in your blood, the clumping ability of your blood fibrinogen is getting-- all these things are sort of shifting. The net of all these things is that you're not oxygenating tissue the way you used to, you're not circulating the way you used to. When you take that, and then you add on top of it sitting or not moving all the time, well, then you've got this perfect witch's brew to accelerate the aging process and the decline of the body. When you start with the highest level, which is, “Well, how do I keep my immune function high? How do I keep my health high?” It's that the body has to do something every day, you got to move every day. You have to take into account the real-world ecosystem.

We're coming back to what really happens over time. What really happens for most people over time, is that they have these long gaps between able to make these real gym campaigns, like, “Okay, I'm going to run a campaign in the gym, and it's going to last forever. Yay.” It really only lasted six months, or a year or two years or five years. Then all the time constraints came in. You need something that in my book, I equate to brushing the teeth. No matter what, every day you're going to brush your teeth, you will brush your teeth, because you can feel the plaque on your teeth, and it's disgusting. You're going to find two minutes every day to brush your teeth no matter what. Taking that idea, if you could just take two minutes and break it up into 20-second intervals and spread them across your day. If you just did that one thing, but you did it every day and did it for 30, 40, 50 years, the difference between your body doing that versus not doing that would be colossal. The adjectives and superlatives could just be stupendous. It would be night and day, black and white, because as we age, we need to make up for the things that are going downhill. The way we make up for that is we emulate the healthiest people in the world. For example, you see field workers in their 90s who were just still working every day. Well, how is it? It's because they're moving every day. I have a toothbrush routine for my body, and I call it the Integrated Interval. I just do it every day. It's basically every day for 20-second intervals, I'm just pushing the body.

I like to do sprints because sprints work the entire body and you have to be young to sprint, so it keeps the body young. A lot of things can work, flexibility-based things can work. I like to do at bedtime. I do a series of yoga flows every day. The difference of doing that versus not doing that is my body is supple and flexible. If we hung out, I'd be running upstairs like crazy and running around like a kid. It's because I just do this one thing every day. My body, my hamstrings, and everything, it's all there. The cool thing about this is it's something anybody can do because there's no warmup, you just do it and then you go back to what you were doing. The irony of that is, it's very tough to do something for two minutes every day. That's almost impossible for most people, but when you break it into 25-second intervals, it's very, very doable.

When you spread them across your day, you're mimicking youngblood because you're forcing circulation across the body. Circulation has everything to do with the body's ability to keep and grow muscle. Poor circulation means that you're going to exhaust your muscle stem cells, you can't grow muscle, and then declining muscle as you age leads to a whole host of problems. So, no matter what, I'm always doing these integrated intervals, no matter what, always, every day. It's kept me young. Then I still do my bodybuilding, beach-centric kind of workouts as often as I can. My path has been so different from most other people, because I had a software. If never done a software, don't, because it'll eat your life. It just ate my life for the last dozen years. My wife looks like someone who works full time because software is just crazy. It's long-winded, sorry about that. I tend to be long-winded sometimes.

Melanie Avalon: No, I love it. Not the same thing, but the hack that I've been doing for probably like 10 years is I wear wrist and ankle weights, like all day. Then when I'm doing the dishes, or go grocery shopping or whatever, it's like resistance training without even meaning to.

Joel Greene: I've seen your picture and you look great. I will bet you that if you had never done that ever, versus having done that, I'll bet you it would be night and day.

Melanie Avalon: A big difference.

Joel Greene: Colossal difference, like a massive difference.

Melanie Avalon: I have been talking about it forever on the Intermittent Fasting podcast. I don't know why more people don't do it. Whenever I go out to the store, I have weights all over me, people look at me funny, but I'm so used to it now. It's been like 10 years.

Joel Greene: I think that's fantastic. This falls under what I talk about a lot, which is there's no 100% answer. What's in my book is a series of 2% to 5% answers. You'll get a 2% bump here, or 3% there or 5% bump here. The thing is, none of them take much to do, but it's the collective impact is on a given day, you're getting a 25%, 30% difference, which played out over a decade is colossal. That's exactly what you're doing.

Melanie Avalon: Yeah, I think it's huge. One more related question. You're talking about the young versus old blood. Then you also talking about young versus old muscle, and you talked about how working out can actually make our muscles older, potentially. What's going on with that?

Joel Greene: Muscles are not a tire with infinite tread. I said that before another podcast, but it's just a good anchor to help us understand that you don't have forever with your muscles. You've got a limited lifetime with them, or limited life cycle. You can use them up faster. It's just like a tire, if you take it to the track all the time, you're going to wear it out a little bit faster. Exercise in general is massively beneficial. Massively beneficial. You absolutely must exercise the muscles every day. What we're getting into though is looking at the difference between the extra 80% of effort that creates 20% or rather that creates 20% improvement in your appearance. To get that 20% improvement in your appearance, it probably takes 80% more effort. The net of that 80% more effort is that you are creating adhesions in the muscle at an accelerated rate and you're depleting stem cells that you need to renew the muscles because you're going to the, well, every time to renew those things.

What this all says is that it's possible to overdo it, it's possible to get the muscles to a place where they just don't renew, and you can see it. You could just go look at some top-level bodybuilders, they're a little bit older now. It doesn't matter what they're on, they can't put muscle on like they used to, that’s because they've blown through their stem cells and all that. In parsing this answer, you need to take it the right way, which is, it's important to exercise, it's even important to exercise intensely here and there or even in moderation, like on a regular basis. There is a cost to continual extreme exercise or continual extreme focus on, maybe like one body part, like the biceps and all that, and it's that, you can blow through them, you can blow through your muscle. I heard Roy Jones Jr, the great boxer said it once, that the way he trained was that he was very ginger in his training because he didn't want to use the muscles up, and that you can use the muscles up. What I've personally witnessed over the years are, this really interesting phenomena of, you see people that have never trained, and then they start training later in life, like 40s 50s and look mind-boggling especially if they go on steroids. Then you see people who have trained all from the time they were a kid, and they look really used up by the time they're in the 50s and 60s, and they just can't gain muscle anymore. There's definitely something to that. Like everybody else, I want to look good, but I put in it in the real-world ecosystem.

Melanie Avalon: You talk about how massage can potentially mimic young blood circulation or doing it after exercise, does it have to be like specific, like a certain type of massage? I get a lot of massages. If I go get a massage, is that going to do it? Or does it have to be like a specific type of muscle massage?

Joel Greene: Well, yes, certain types of massage have been shown to produce results that they're different. In my book, I talk about a very specific type of massage that's been shown to grow muscle in the absence of exercise but suffice to say that post-exercise you need young circulation. Circulation and muscle growth are one in the same, like you need-- In fact, one of the ways that you can stimulate muscle growth and age muscles to take EPO, erythropoietin, which just mimics young blood because you get this expansion in bloodline.

Melanie Avalon: What is that? EPO?

Joel Greene: Yeah, erythropoietin.

Melanie Avalon: Can you buy that?

Joel Greene: How about no? No, that's what Lance Armstrong got kicked out of-- It's the Lance Armstrong’s drug, but it's--

Melanie Avalon: That's how much I know about this. Okay.

Joel Greene: Yeah, well, I'm the one that got ask. My knowledge is very limited as well, but you'll find it in, it's under the umbrella of performance enhancement substances. A lot of bodybuilders take it because it expands the blood volume, makes you look bigger, but it also gives you better endurance. I've never taken it. I know people who haven't been around the industry a long time. Where it's got a new home, I think that is very interesting is in the hands of a longevity practitioner. I would never take it unless it was with a practitioner because there can be very serious complications from it. I think in the hands of a good practitioner, it's a very fantastic tool to keep the body young as we get older, but what it gets down to is, going back to massage, circulation. Somethings better than nothing after massage, but again, it's what, when, and how.

The when is that post-workout, there seems to be a window of sort of max inflammatory signals somewhere around that six-hour mark, 6 to 12 hours. That's when certain proteins in my book, I mentioned them, like ERK and 1/2 are at the max. What they're doing is they're recruiting immune factors to restore muscle. During this period, that's when you need it. Then the what is there's definitely different types of massage. High-level bodybuilders and people like that all use what's known as bodywork where they're actually getting someone who knows what they're doing to go in and remove adhesions in the muscle. My friend Ron, he does it on a regular basis. He's just always pumped. I started doing something similar just on my own. I noticed the difference was that, I went through this period where I was always pumped when I was younger like I was never pumped and I couldn't figure out. Then, well, just circulation, and now post-workout, I apply like different types of massage and things. I'm always pumped again. It's purely just circulation.

Melanie Avalon: Like a vibration machine, does that support circulation, do you know?

Joel Greene: Yeah. Are you talking about the ones just--?

Melanie Avalon: That you stand on or sit on?

Joel Greene: Oh, yeah, good one. I'm not 100% sure about that. Don't know. I haven't studied it. I did an article on, that was like a long time ago, like 2007. I haven't really looked at them in a long time.

Melanie Avalon: One more question. You're talking about, like, what's going to become mainstream, or-- one thing I love that you talked about was you said that there were four words that were going to become mainstream that you were prophesizing, and it was AMPK sirtuins, NAD and CD38. I feel AMPK sirtuins, NAD are lot of talk around that. I had not heard of CD38. What is CD38?

Joel Greene: In the immune centric approach to health, immune cells and immune cell metabolism have this vast influence over the body as a whole. What we see on immune cells are these things called cluster of differentiation, or CDs. What these are very specific receptors that activate in response to different stimuli, mostly in immune cells. CD38 is one of those. CD38, you see it in immune cells. When we activate CD38, we see this elevation of-- we can get NAD to elevate by activating CD38. We see CD38 and NAD levels like that opposite ends. Excuse me, I've got it backwards. We need to suppress CD38, we need to inhibit CD38.

When we see high CD38, we see a low NAD. When we see a low CD38, we see high NAD in the body. Really it gets to going back to, I talked about macrophages, certain types of inflammatory macrophages can use NAD, it gets to macrophage metabolism. When the inflammatory macrophages are gobbling up all the NAD, then there's not going to be NAD for other tissues. When we suppress CD38, when we suppress that receptor, then we see NAD levels go right up. All that says that there's a number of ways to skin the cat of repleting NAD, we can do it in a number of different ways. We can do it by restoring sleep, we can do it by mitigating CD38, we can do it by supplementing with things like nicotine herbicide or nicotine mononucleotide.

Melanie Avalon: How do you feel about those NR and NMN supplementing them?

Joel Greene: I think strategical used, they're amazing. Like we talked about, they under certain conditions, if you have a lot of senescent cells, if you have inflamed fat, we just want to go right to those things, you'd want to probably initiate flushing senescent cells and mitigating inflammation first before you did that. Under normal circumstances where you have an ageing body, the administration of those things can be a great adjunct. Particularly, you see some practitioners now doing like IV NAD, which they swear by. Yeah, I think it's a toolset and used correctly, it can be fantastic.

Melanie Avalon: Like I said, I interviewed James Nestor. So, I read Breath, I was like, “I'm going to get my deviated septum fixed.” So, I had surgery.

Joel Greene: Huh. Did you really?

Melanie Avalon: Yes.

Joel Greene: Wow. Well, that's funny.

Melanie Avalon: What's crazy was, was really upsetting because they're like, “You can't lift anything heavier than an iPad for a week. You can't do sauna. You can't do exercise. You can't do anything.” I felt like I was dying. I was like, “What can I do? I can't do any of my normal stuff.” I was like, “I can take NR and NMN.” I wasn't taking it because I've been taking it a little bit in the past, but I'd stopped. I was feeling so awful after the surgery, and it could have been a coincidence, but I high dosed it because I was feeling so terrible. It could have been a coincidence, but I saw massive improvements just in how I felt. I'm like, “Oh, I want to take this for life,” but I have a tendency to go extreme. I probably shouldn't do that.

Joel Greene: I hear that quite a bit. A lot of it has to do with the dosing. What I've heard a lot of people report is it the lower doses, they don't feel too much. But in the very high doses, they do. What did you notice?

Melanie Avalon: I felt like death, just death. I've never felt that before. I was just laying on the couch, I couldn't move, everything was completely exhausting me. Then I high-high dosed it and my energy just started coming back. Like I said, could have been a time thing, could have been coincidence, but I don't know if, James Clement, he wrote a book called The Switch. He's really into that whole research. I was asking him, I was like, “Could this really have made that much of a difference?” He was saying, they've done studies on, in his work like high dosing it and found that it significantly improved NAD levels, pretty fast.

Joel Greene: What sort of dose levels like in the gram range?

Melanie Avalon: I have to look it up.

Joel Greene: Was it NMN or NAD? Excuse me, or NR?

Melanie Avalon: I had both. What I high dosed was NR. Do you have a preference between the two?

Joel Greene: And the NMN, probably. Yeah. I'm curious about the high dosing of NR what your experience was, for sure.

Melanie Avalon: He said, and his own experience, he took 1000 milligrams of NMN and 1000 of NR a day for three days, erase his whole blood NAD levels by 6 to 30-fold.

Joel Greene: So, he was taking both?

Melanie Avalon: He was taking both. I don’t remember if I took both. I told him I've been taking 250 milligrams NR with dinner, 650 NMN throughout the day, but I think right after the surgery, I have massively upped that.

Joel Greene: Yeah, that's along the lines of what I've heard. Also, we need to get into the grand doses, and that's not easy, for just financially, it's not easy.

Melanie Avalon: I was like, “There goes my NR.” Well, okay, I want to be super respectful of your time. This has been so amazing. You mentioned at the beginning, like we didn't even talk about, I don't even how you say it, pexophagy and peroxisomes.

Joel Greene: Pexophagy.

Melanie Avalon: Pexophagy, and so many other things, membranes. Is there anything really big that you wanted to touch on, that’s like speaking from your heart?

Joel Greene: Oh. Gosh, let me think about it. Well, I think it's this. I've come a long way, over a number of years doing this stuff. I've always, always just been concerned about what was really true as a consumer. My road was one of really getting to the reality of how things work, and what's really true over time. The unfortunate aspect of the ecosystem or the thought sphere that we're in, is that there's a lot of fantasy and a lot of things that don't work overtime. That it's very easy to jump on fads and jump on things. What I've seen a lot of is people hurt themselves long term by doing things, that we're coming from a place that wasn't really very well informed. In getting to a place where you're going to get the result you want long term, you have to put your health first. Appearance is very important, but life's not a bodybuilding contest. It's not the ultimate driver of things. You need to really reframe things and understand that most people live in the real-world ecosystem, and that ecosystem has very significant challenges overtime to maintain anything.

To get where you want to go, it takes a very large rethink, and you have to be open to much of the information you've been given, really doesn't work overtime. It just doesn't, because it's not coming from the real-world ecosystem, or it's not based on how things actually work. All that takes us to a place where you need some things to hang on to. I try to put those things forward, which is that health is balance, imbalance is disease. Foundationally, a lot of the things that I found over time were most true are things that just make sense. Things like that, at the end of the day, our diets need balance over the long term. It doesn't mean you can't have forays into certain extremes, but by our diets need to be balanced. Most of the things that we think we know, don't actually work that way, like fat loss doesn't work the way we think it does. You really just have to be open to rethinking a lot of things. Everything I'm doing is coming from that place, it's coming from that place of like, what's going to really work overtime? What's going to solve the problem in the body?

I've had people in my family, like my mother, my father, other people that they've really struggled with health issues. I've just always been concerned with what's really true. For the listener, who is trying to figure all this stuff out what's going to really matter is keep your focus on the long term. Keep your focus on the long term, because it's very easy to get short term results by a lot of different methods, but very often they backfire. You got to keep that long term perspective.

Melanie Avalon: This is so incredible. I mean, your book, everything you said, just resonates with me so much. I know my audience-- See, audience, now you understand why it decided to be a two-part episode? We only slightly scratched the surface of everything that's in the book. Friends, get The Immunity Code, it's all in there. Like Joel was saying, well, there's the whole paradigm reframe of what is truth, what's actually happening, what's going on, there's the science of all of it. There's actually a ton of step by step hacks, protocols to implement, really fascinating things like, we didn't even talk about offsetting, but how you can have different meals that create different effects as far as you think excess calories, but you can actually support weight loss and hacks for AMPK and for NAD and stubborn fat. Really quick tangent, one thing that's always bothered me in the health and wellness and diet sphere is people will say, “Oh, you can't spot burn fat.” I've always thought, “Well, if you put something on the fat that tells the fat like-- that changes-- that makes the fat more likely to be burned or changes things, why would you not be able to?”

Joel Greene: Well, think about it this way, you 100% don't store fat equally at all junctures in the body. That's just simply not true. You start fat at different rates in different areas of the body, different things like insulin resistance and things like that, hormones govern different fat depots. If you don't store fat equally, you certainly don't burn it equally. Everybody knows that's true. When you're burning fat, you have problem areas [unintelligible [02:33:23] least fat. Well, those problem areas have physical, biochemical differences from other areas. It's entirely possible to target those differences. The easiest example is insulin resistance. It's entirely possible to target insulin resistance in problem areas, like your belly fat, just using exercise-induced muscle contractions, in conjunction with other things, like cold and the way you time things and the foods that are around that. If I can do a plug on-- I have a course that, by the time this is coming out, it should be out, called Immune Centric Fat Loss, where we step through again with all this stuff from an immune centric point of view. It's the other half of the book. The book would have been 700-800 pages, but I put all that junk in the book. It's meant to deal with these things. It's meant to deal with all this stuff, so that's my little plug.

Melanie Avalon: For listeners to best follow your work, learn more information, what links can we put out there?

Joel Greene: Oh, just go to veepnutrition.com. Everything is there. Follow me on Instagram, it's at @realjoelgreene. That's green with an E on the end on Instagram. I just started my Insta this year. It's taken off. I try to do my best about it-- I get a lot of questions. It's getting words almost impossible to answer all of them, but I do my best, so you never know. I might interact there. I'll do my best so, it's the best way.

Melanie Avalon: Wait, I want to follow you right now. What was it?

Joel Greene: @realjoelgreene.

Melanie Avalon: Instagram, it scares me. I'm really big in my Facebook group and all of that stuff, but Instagram, I don't know, intimidating. Well, this has been absolutely amazing. Listeners, again, check out the show notes, the show notes will have a complete transcript of everything, which will definitely, definitely be helpful. The last question that I ask every single guest on this podcast, and it's just because I've come to appreciate more and more each and every day how important mindset is surrounding everything, which is full circle. We talked a lot about that. What is something that you're grateful for?

Joel Greene: I'm grateful to have grown up in America. I grew up poor. I had a single mom, she had three boys, one of them with down syndrome. We saw a lot of challenges growing up. If I had been born any other place, other than this country, my life would be completely different. It's only because I was born in this country that I've had the opportunities I've had in life to educate myself. To meet just amazing people working in an incredible industry and just contributing to the world. We've got something really special in this country, and it needs to be protected and preserved because there's no other place like it. I'm just grateful for this country.

Melanie Avalon: Nobody's ever said that. That's a really wonderful thing. Thank you so much. This has been absolutely amazing. I'm so grateful for your work for what you're doing. It's such a needed paradigm shift and you're providing such valuable tools that people can actually implement and make real lasting change. Thank you so much.

Joel Greene: Thank you, Melanie. I'm super grateful. So grateful and hope we can chat more and maybe if you get out to California, or vice versa, we'll hang out.

Melanie Avalon: Oh, yes, please, that'd be amazing. I feel I could talk to you for 10 hours. We clearly can talk for three hours, so we got that covered. Thank you so much, and I'll talk to you again in the future.

Joel Greene: All right. Thank you so much.

Melanie Avalon: Bye.

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