More than Just Detox: AMPK and Nrf2 as Fundamental Pillars of Longevity

Christopher Shade, PhD

Oh, thank you so much. Well, I can’t wait to do the same. After my house burned, I lost my little sauna, so I’m getting a new one. I’m getting a clear light sauna so I can put that in my bedroom.

Matthew Cook, M.D.

Oh, good, that’s what I have also.

Christopher Shade, PhD

sauna and binder.

Matthew Cook, M.D.

Now what happened? Tell us what happened to your house.

Christopher Shade, PhD

The Marshall fire out here in Boulder County, there was a day where the winds were 60 to a hundred miles an hour all day. And this wildfire broke out. This was in December, usually don’t get fires. And it blew right through the town of Louisville and big parts of Superior and Broomfield. And my whole neighborhood was daunted just to ashes.

Matthew Cook, M.D.

That’s crazy. Well, like the Phoenix somehow you’re gonna rise maybe.

Christopher Shade, PhD

Rising up again, I got a new house, I got all new stuff. Everything’s cool, my reset now.

Matthew Cook, M.D.

Yeah, exactly, that’s the bio reset.

Christopher Shade, PhD

That’s it?

Matthew Cook, M.D.

Life reset.

Christopher Shade, PhD

Yeah.

Matthew Cook, M.D.

So then the title of this talk, I love the title, More Than Just Detox. AMPK and Nrf2 is fundamental pillars of longevity.

Christopher Shade, PhD

Yeah.

Matthew Cook, M.D.

And this is a peptide summit, but fundamentally what’s happening with peptides is we’re using them to influence and modulate biology. And so then sometimes to really do this, we have to get into the weeds and understand the biology a little bit. And Chris you know, there’s no one better than you at that. So, give me a little bit of introduction of where we’re gonna start. How did these influence our health and where should we get started?

Christopher Shade, PhD

Yeah, well, we have this thing I needed to see it on our website we call the longevity wheel. And it was like, what are the things that you can intervene with supplements and affect different aspects of longevity and maximize longevity? And you’ll see things on there that we think of that become big in longevity work. Like senolytics and senescence cells, telomeres. But up at the top of it is Nrf2 and AMPK. And to me, that’s the central pillar. Now on a loose level you could say, “Well, it’s detoxing and cleaning everything up.” And if we keep everything clean, then everything works well. And really that is pretty true. And I did some A4M lectures recently. And was saying, “I used to be…” Remember when you met me and were back at the A4M expo and I’m selling all this detox stuff. For mercury detox, and you were… All flooring poisoned from being an anesthesiologist. And I was like, “Yeah, but the cool people are really up the front, they got stem cells and all this stuff.” But it’s like when you look at like, how does this cell become senescent? A toxin will go in, create damage to the telomeres and that’ll create mitochondrial dysfunction. 

And this cell goes into a senescent phenotype. So if Nrf2 is up and working, you’re protecting the cell all the time from these incoming toxins. And making sure that they don’t take you down this path into death. And then of course we know with senescence, then these cells start spreading these expanding waves of inflammation and expanding fields of inflammation. Maybe are the key to aging and why we’re going downhill. And so how do we stop these things? And up at the top of the game, we’re using Nrf2, turns up all of our free radical and environmental chemical protection. And its brother pathway as AMPK. And AMPK is what we activate when we do a keto diet, when we carb strict, when we intermittent fast, when we water fast. All these times we take away instant carb access, we block anabolism turn up catabolism, and go and have this inner cleanup that we call autophagy. So Nrf2 is cleaning up the chemical mess, and autophagy is cleaning up the biological mess. Now these are maybe they’re old dead mitochondria, or misfunctioning mitochondria. Maybe it’s the endoplasmic reticulum, the Golgi, maybe it’s whole cells. It’s fatty deposits that are releasing inflammatory cytokines. 

If it’s fatty liver, alcoholic or non-alcoholic, those resets are all part of autophagy which is AMPK activation. You stop building and you use what you have. That’s mobilizing fat, including burning up fatty deposits like in the liver. So you’re using that for energy, it’s also making more efficient use of glucose. You got more glucose transporters, you got lower insulin resistance, higher sensitivity. And then you’re breaking down those little cell parts to reuse amino acids. So those two fundamentally go together. And if you don’t have those two taken care of, you can try to use some senolytics. And you can try to spend a lot of money on telomerase activators. But it’s just not gonna work all that well if you don’t have those fundamentals in place. And when those fundamentals are in place, there is so much clean up and remodeling that comes along with them, not just the autophagy but even unfolded protein response. Unfolded protein response, you are making proteins all the time, and you make a bunch wrong. 

And you got little sensors in your cell to see that they’re wrong and you kind of stick ’em over in the corner of the cell, and they build up. And if they build up so much that they trigger an uncontrolled unfolded protein response, it pretty much kills the cell. But if you’re going through autophagy a lot, you’re taking these old piles of bad proteins and breaking ’em down in a controlled way down into their constituent amino acid. And all these build ups of things. Fatty stuff, old cellular debris, old proteins. Those are all inflammatory triggers and part of the spreading the inflammatory field. And then at a cellular level when it gets memorialized, is when it goes into the senescent phenotype. And then once you have a senescent thing, you either gonna kill it, or you can reverse it. And restoring the cellular Mallu, the redox poise and the cleanliness of the cell, the antioxidant levels can pull the cell out of senescence without going and killing the cell off. So it really… If you don’t start with those, you’re just fighting against the wind.

Matthew Cook, M.D.

I love that. And so then that gives you a rough framework, and that’s why I wanted to kind of get you to kind of highlight this stuff. So then what are your favorite strategies then to do this?

Christopher Shade, PhD

Yeah, well, there’s sort of short term and long term. So for instance, you were talking about your long term cleanup, of having the binder on there. So what are Nrf2? So Nrf2, you can trigger Nrf2 and it is outside of the nucleus. It’s a protein that’s held outside of the nucleus by another protein called KIP1. That’s sitting there on an actin filament like a rope. And when you trigger, KIP1 to change confirmation, Nrf2 goes into the nucleus, translocates in. These are called nuclear transcription factors. So transcription is genes. And so the Nrf2 goes in and it targets a family of genes to all turn up their transcription. This family all has a common promoter region. It’s kind of like an address on a gene, and it’s also like the start point of it. And it’s called the antioxidant response. And the it’s the response of the cell to create antioxidant activity. So all these genes, they good for glutathione synthesis, glutathione reductase synthesis, glutathione transferase superoxide dismutase. So they’re free radical and toxin cleanup, and the transporter’s up. So it brings up all this chemistry to get stuff out. So there’s triggering that to happen. And say, we’re gonna do some sort of detox. Well, we want to take something to trigger that to turn up. 

Now, the presence of the toxins themselves can do that. But if you have a chronic accumulation of toxins, you become habituated to that, and you need some other trigger. And you need a trigger that up regulates it without creating too much damage. Because in reality, these compounds that do that, are light hormetic toxins. So you take like a real strong one, like sulforaphane. sulforaphane is a very strong free radical generator, really strong electrophile. So you want something to do that without really damaging you. Arsenic, methyl mercury, they all do that, but they have a lot of collateral damage. So we want to be able to up regulate Nrf2, get the cells to take toxins, throw them into circulation. Then you need your liver to grab them from the blood, dump them out in the bile and get them out to the GI tract. That’s where the binder comes into sort of grab and hold all that stuff. 

And out through the kidneys, into the urine. So you want to coordinate these up regulations of Nrf2 with some shepherding of these toxins out. So, then if you’re doing like programs, like you’re doing a program with us. Maybe you’re using our liver sauce and binder. Maybe you’re using another form of lipoic acid is just strong enough to up regulator, quercetin is. But when we make something like liver sauce and binder for push catch liver detox, one is working on up regulating the cells Nrf2 with lipoic acid, number one, then DIM, course and luteal, number two. And then coordinating that to bile flow, because the way you dump toxins outta your livers on the bile. So if you can stimulate some bile flow before you come in with binder, you’re going to dump a bunch of those toxins out. Conversely, when you block bile flow, if you have cholestasis, you cannot move toxins out at all. So that’s important thing to bring together. So for doing one of those, we may do a formal detox. We’re gonna start you at a dose, where over a couple of weeks, we’re gonna march you up a dose. You’re gonna be doing something like five days on, two days off. 

Or 10 days on, four days off. That’s this formal detox. And getting up to high levels, you’d be bringing in glutathione with that. Maybe you need EDTA to get rid of some lead. You designed for the things you’re trying to move out. So that’s like, “Wow, I’m toxic, I gotta get this stuff out.” But long term is using smaller amounts of these over periods. And eventually we wanna get compounds that overlap. So where’s the AMPK side of this? So AMPK, like use rapamycin is the AMPK activator. Metformin is AMPK activator. Metformin probably that’s the most notorious one. Rapamycin, I’m sorry, that’s more of senolytics and autophagy. But they’re both doing this. They’re all both working on this. Blocking anabolism, turning up catabolism, turning up autophagy. And that in the naturals you’ve got, Berberine, quercetin, Resveratrol, pterostilbene, silymarin. That’s why it works so well on liver. Kind of targets NAD, sirtuin and AMPK activity in the liver. We also use a little bit of DIM and cinnamon. And we have a product there called AMPK charge, total co-keto before six. Now that works more on this pathway. So in a couple hours, you’re generating ketones. 

Now, how do those overlap? When AMPK is active, Nrf2 is way easier to activate. So you’re taking AMPK activators, Nrf2 goes up much more easily. So we like a lot of these things to go together. And in fact, in our liver sauce, there’s both AMPK and Nrf2 activators. And we figured this all out. Once Cheng Juan was doing a fatty liver study. And in one to two months on this simple two part detox, he had 80% resolution of fatty liver. And I was like, “Wow.” That’s when I started looking at AMPK and its relationship to Nrf2. Now one of the easiest things that anybody can do to get AMPK active is fast. And it’s not like you got a fast for four days, even if you’re intermittent fasting, that activity is going to be unregulated. And then if you overlap some of these compounds that hit one Nrf2 or AMPK or both, then you’re gonna be able to get into this metabolic cleanup phase. So it’s really easy, especially if it’s not a woman of childbearing age and people or her age. It’s so easy to intermittent fast, not eat until one o’clock and put a bunch of supplements in early, that activate these pathways. And you can activate ’em then you can come in with some carbon or not. There’s a lot of different ways to go about it, but it’s gotta be something that’s on our pallet of things to do, at least a couple days a week.

Matthew Cook, M.D.

Okay, how much liver sauce do you recommend doing to get that activation as a push catch? And then tell me about that push catch. ‘Cause I think that that’s been such amazing thing for our patients.

Christopher Shade, PhD

It’s such a simple… Little box got one bottle of a liquid called liver sauce. It’s like A one for your liver and you got hose that on there. And then some packets or a bottle with this charcoal, clay, chitosan, binder blend. And the liver sauce combines traditional bitter compounds that are found in our product Bitter X. This is gentian, dandelion, solidago and myrrh. Myrrh’s an awesome one. In that’s the primary bitter detoxifier. And it’s used in every gynecological formula to clear stagnant Chi or blood out the uterus. Well, it also clears stagnant bile out of the liver. So you got that in there, then you got a histamine. Well, this next blend is DIM, quercetin and luteolin. Now that does a whole bunch of things. When I first bought it in there, it was a mass cell stabilizer. And it does, ’cause you’re gonna move these toxins around. And if it winds up mass cells and inflammation, inflammation blocks detox. So there’s all these things that get in the way. 

Cholestasis blocks detox, inflammation blocks detox. So we have to make sure we’re not winding things up. And so we put those in there, but turns out those are also good Nrf2 up regulators, and they’re good AMPK activators, and they’re good senolytics, and they’re good even uric acid blockers. They do a whole bunch of things in there. And then the last two ingredients are silymarin from our Nano Milk Thistle, and our lipoic acid, which we put into the whole nano particle format. So there’s this combined blend that’s up regulating cellular Nrf2, activating AMPK, going into this catabolism helps you get rid of this cellular debris as well as the chemical debris. Then coupling that to bile flow. And that’s getting the liver to grab things, pull it into the liver and dump them out. So the bile transporters and toxin transporters are the same things. While one’s called the BSEP, bile salt export pump just moves bile. 

The other is called MRP2, which moves bile salts and conjugated toxins. Like mercury glutathione conjugate. And then the MDR moves phosphatidylcholine into the bile to keep the bile fluid. So usually we will add in extra PC as well. There’s some in the delivery system, but often we add more in. We might add some glutathione. But even just that simple basic push catch with Nrf2, MPK, bile flow, dump everything down. And in a half hour later, you shake up the binder mix, which is charcoal, zeolite, chitosan, which is a molecular mimic of welco. IMD, which is our proprietary metal binder, and some Acaia gum and PectaSol to modulate the immune system in the GI tract. So push is liver sauce, move it from the cells to the liver, out into the bile, catch with the binder half hour later. It’s just amazing how it just ties up this cycle of detox. And you’re not left with stuff running all around your body all the time. And it works that way because of this nano particle delivery. We have these, 15 to 15 nanometer lipid nano particles. 

Either liposomes for water symbols, nanoemulsions for fat symbols. These things get into your body in just a couple of minutes, they’ll peek in your blood 15 to 25 minutes, and activate all these processes and coordinately activate them. It’s not like, I’m taking all these pills and one absorbs in 40 minutes and one absorbs over six hours, and one absorbs later. Where all these different processes aren’t coordinated. This is more like injecting it in. So all the things happen at once and activate everything. Then the binder clears it all up and ties this little cycle of detox into a neat little bow. Now, if you’re sensitive, you can start at a half dose per day. So a half teaspoon liver sauce, half teaspoon of binder. 

And you can do that once a day, then go to twice a day, then go to a teaspoon twice a day. I have people when they’re really flushing it out, doing three teaspoons, three times a day. Really big dumping stuff out. So that’s the titration up of the dose. Start low, get used to the process, and move up to higher dosage. You want to just go as high as you can, as soon as your body can handle it. Now there’s other things you can throw in to modulate that. If you need CBD to bring down inflammation, Cat’s Claw for some late viral stuff. There’s a all kinds of toys you can throw into the mix there injectably. But yeah, that’s push catch. And that’s just the core really essence of detox.

Matthew Cook, M.D.

When you add PC in, how much would you add in?

Christopher Shade, PhD

I do one to two teaspoons of either pure PC, is one product that’s just… It’s a soy sourced phosphatidylcholine, very pure, no soy compounds. The other new one is called membrane mint. That sunflower PC with Astaxanthin and tocotrienol and ahi flower. That one has net anti-inflammatory activity and more of a soothing effect on the vasculature. But one teaspoon of either those with your liver sauce is a great addition. Glutathione, maybe five pumps like that. Because it goes well with the number of pumps in the bottle and the number or teaspoons in the liver sauce.

Matthew Cook, M.D.

Okay, nice. And then let’s say I’ve got two people. One person’s pretty toxic and wants to do something. And so then we would put them on an algorithm like that. And I buy the way people… I use this algorithm for people all the time. It’s probably my favorite algorithm for detox. Let’s say I got another person that’s interested in antiaging and wellness. And they said, “Hey, if I could detox myself…” And let’s say they were like me doing a sauna. Could that be something that they could do year round? Or what frequency do you cycle on and off a push catch program? Or how do you think about that?

Christopher Shade, PhD

A lot of it comes down to how people are. Some people are very habitual and they want things on a certain schedule. Other people go all in and then come all out. So you gotta kind of see how they like to be. But if they’re getting into a longevity protocol, we just did this three month treatment sequence, which we believed was like your initial movement into anti-aging. And we did true diagnostics, biological age tests before and after. And the first month was push catch based. It was push catch with glutathione and Cat’s Claw. The second month we switched the push catch away from liver sauce and went to AMPK charge. So this was stronger AMPK, stronger autophagy and stronger senolytics activity. But still with the glutathione, the binder, and the membranement. And in retrospect, I’d put the membrane stuff in the beginning. 

And then the third month we took the binder and glutathione out and it was… Oh, and for month two and three, we put in the NAD platinum. In retrospect I kind of want the NAD in the PC all the way through. But we were to see this very significant reversal of net biological age. We also saw a very significant slowing of the rate of aging by the DunedinPoAm algorithm. The net biological age, we used the original Horvath clock, and we saw specific changes in B cells, monocytes, and natural killer cells in the epigenetic markers of those. So I did like this startup. You’re gonna get into anti aging, we’re gonna do your formal detox and metabolic and mitochondrial rehab. 

Then after that, what are you gonna do? You know, “Oh, let’s do two rounds of detox every weekend. Or every quarter, let’s do a two week detox. Or a full month, once a year.” I integrate them in just kind of as I go. And like when I’m more toxic, I’ll shift over and be like, I’m gonna do liver sauce. When I’m less, I’m doing the AMPK charge pretty constantly. At least a couple times a week, because that really goes good in the morning, gets you making ketones by about… Within not too long, your blood ketones will be up over 0.5 despite eating carbs the night before. And so you get a period of the day, there’s no thistle in there that’s activating liver. There’s some bitterness to the berberine. The quercetin, it’s just not strongly liver detox as the liver sauce. So I’m doing that a couple times a week and fasting in the morning. And then, when I have time, I’ll do some push catch with the sauna. And that, you do liver sauce, sauna, binder.

Matthew Cook, M.D.

I love that. So then that’s exactly what I do. And so then this is as you’re out there kind of thinking about incorporating these things, that what Chris said is great, because I like the idea that when you’re not toxic, then you’re working on kind of a certain strategy. But then all of a sudden you go, “Oh, I was just traveling and I ate…” Like, I go so far outta my way to eat good food, which I got to cook dinner for you a bunch of times. So-

Christopher Shade, PhD

Yes.

Matthew Cook, M.D.

Versus when you’re running around and you’re eating bad food at a meeting. Then I’ll do… It’s kind of I’m a huge fan of the push catch, I think it’s a wise strategy.

Christopher Shade, PhD

Yeah, now, it’s really great. And so sort of your long term, you’re always pushing AMPK, NAD and sirtuins. And you’re keeping yourself on that. And then when you’ve gotta clean up and let’s not forget the moldy hotels, all of the… Think of how much antimicrobial sanitizers all over the place. Everything’s hose down with a coating and this, that, or the other thing during COVID. So yeah, when we travel, we just get dirty. And then we come home and we gotta clean up.

Matthew Cook, M.D.

Now then talk me through then your perspective. ‘Cause this is one of my favorites. On sirtuins, NAD and the NAD cycle, and how you like to work with increasing NAD.

Christopher Shade, PhD

So you gotta figure out that the individualist part is the balance between NAD and methylation. So how are we gonna push NAD? If we’re dealing with teenagers and 20 year olds, you just give ’em a little B3 and everything’s cool. You’re dealing with older people, you gotta go to these higher form. So it’s nicotinamide mononucleotide animun or NR, nicotinamide ribosome. When you’re doing that, it becomes very quickly NAD and then it activates a sirtuin, and the sirtuin, or it activates CD38 or activates parts. And you’re left with nicotinamide. Now, nicotinamide starts pulling up and it blocks the sirtuins. so we have to be feeding always the precursors in and draining the reactants out of the system. How do you get rid of nicotinamide? You methylate it with SAMe. And then that’s methyl nicotinamide be peed out. Okay, that’s great. Except what do we have then? We have S-adenosylhomocysteine, and then homocysteine. If we just drive NAD all the time, we’re net shifting ourselves over to high homocystine. 

So then we have to turn up the methionine and MTHFR cycle, the folate cycle to regenerate S-adenosyl methionine. So that some combination of TMG, B2, methyl B12, and maybe a little B9 and B6 to help catalyze all that. So you need to balance those. So, we sell individual products. We have our liposomal NMN called NAD + Gold. And then we pair that with our liposomal methyl charge. And you can mix those the way you want. And on average, for the average methylator, it’s two NAD + Gold to one methyl charge. And that’s the same ratio that’s put into our NAD platinum, which is as the NMN with methylation co-factors and quercetin and resveratrol for sirtuin activation and some senolytics activity. So that’s a sort of one stop shop. Now, I tell you an interesting story. My partner Tony was just here. When he got started on NAD, he came and he lived with me for a couple of days. And I noticed he had some little neurological things. 

He’d just sort of phase out a little bit. And be like, “Wait, where am I?” And he started doing this two to one entity gold methyl charge, and I noticed they didn’t get better. And I thought they would. And if anything, they seemed to get worse. And I gave him more methyl charge, made it one to one, and that all disappeared completely. And he’s been like super strong, super good. And he has a family history of Parkinson’s. But that something ties in there with that need for more methyl groups there. And those two definitely has to be balanced. And when you get both of those working high. NAD cycles, methylation cycles, you have a really high functioning system there. And so I come in with those pretty much daily. And then intermittently, less intermittently liver sauce, more intermittently AMPK charge. 

And then, also more intermittently this new formula that we call Longevity Elite. Which has the specific Astragaloside, Cycloastragenol, and Astragaloside IV. So cyclo, there’s a lot of data around telomerase activation, but there’s great data of it is senolytic. And Astragaloside IV is up regulator. So for kidney and brain regeneration. and then it’s got a little bit of… It’s a really fun, like, you look at it, it’s like an adaptogen formula. ‘Cause there’s Ginseng, there’s Astragaloside, He Shou Wu, Ashwagandha in it, oh, well, that’s awesome. But then there’s a shot of pregnenolone in it. And so pregnenolone, is that hormone that becomes all the adrenal hormones or the sex hormones. And so you get a little boost to you. It can go become anything, and it can do that under the influence of all these adaptogens. 

And then you have those very high and pure Astragaloside compounds. And so when you look at the data around, resveratrol, sirtuin activator, Ginseng, sirtuin activator. We look at the adaptogens, all of them have the steroid backbone as your hormones, same steroid backbone. Why was that the antiaging medicine in China and India for 5,000 years with analide from ashwagandha, they look like a hormone. Astragaloside look like a hormone, ginsenosides look like a hormone, gypenosides they look like a hormone. And so that formula was all about putting your prototypal hormone pregnenolone in with all the adaptogens. And then you, “Oh, they raise energy.” How? By increasing mitochondrial activity. How? ‘Cause there’s sirtuin activators. So now we have these pure compounds and we have these plants. 

And I like these blends of a whole plant extract and pure compounds. I remember Dietrich Kling Hart saying to me once, he was just talking about vitamins versus herbs. And he said, “Vitamins represent what we do know, plants represent what we don’t know.” And now we know more and more and more about the specific compounds in the plants, but you start extracting this one, that one, the other one. Sometimes you need the whole plant to bring you some of the things. Like Ginseng’s especially, something that’s been used for thousands and thousands of years. So net, net, I gotta figure out what my balance of NAD and methylation is. And then I have to feed in things that are… And a lot of these things are AMPK activators, and sirtuin activators, and senolytics like quercetin. So soon… Oh, and then it’s also somewhat of an Nrf2 regular. So soon you see that you’re hitting a lot of these doors and then you have to have these little campaigns that focus on something like drainage.

Matthew Cook, M.D.

Okay, that’s amazing. I totally agree, and there was sort of a push that came maybe from the beginning of medicine that was really pharma based. And with the idea that maybe there was a plant that had some molecule, and then basically if we could extract and have a super concentrated high amount of that molecule, that, that molecule might help you. But in many cases, the way that it exists in the plant is potentially better for you. And then if you can do that, and then you put it in these liposomal formulas that make them very absorbable, and then you’re blends. I think of you sometimes more of a magician chemist. Because the harmony and the synergy of that, is like the equivalent of a Michelin Restaurant, but from a perspective.

Christopher Shade, PhD

Well, thank you very much. And yeah, it’s that blending that ties everything together. You look at some of the data on monotherapies, like they tried to make a drug out of resveratrol. And they fucked some people up. And it was just too much of a single thing and not blending it with other stuff. In fact, so how does sirtuins get activated? Sirtuins they got two spaces for activators to come in. One takes NAD, and it won’t go without the NAD. And the other takes these sirtuin activating compounds like resveratrol, quercetin, dasatinib. And so NAD is always up regulating sirtuin and these sirtuin activating compounds are sort of hyper activating it. But if you just throw in a you’ll actually pull NAD out of the mitochondria to activate the sirtuin and starve the mitochondria then. And so then you’re forcing something to happen that if you had everything taken together, it would work great. So if you have the NAD in there, and you’ve got the balancing methylation, and then you’re going after these sirtuin activating compounds, everything’s gonna work really well. And so there’s the blend that way where we know which pathways we gotta blend. And then there’s the like, “Well, this one I’m putting whole plant and that’ll take a pure compound.”

Matthew Cook, M.D.

Okay, now just to go back to 101, educate us on what the sirtuin super family is, and what’s happening with that.

Christopher Shade, PhD

Yeah, sirtuins are DSC leaders. And acetyl groups are sort of on and off switches for a number of things. And you tend to get one way or the other. So deacetylation activates families of biochemistry that are very efficient metabolically. So you’re conserving energy. You’re burning things more cleanly. You have insulin sensitivity, not resistance. You’re a little bit more catabolic, but you’re clean. It’s caloric restriction. In fact, caloric restrictions effect on longevity is a sirtuin dependent effect. When you caloric restrict, you shift to more NAD plus over NADH. Which gives you more sirtuin activation, which gives more insulin sensitivity, which burns up more stored fat, burns up more stored glycogen. So you’re moving onto a clean burning side. And there’s whole gene sets that you’re turning on and off in the process of this, to keep yourself all the way to this side. Whereas when everything’s acidulated, you turn that down and you shift over to a side that is more inflammatory and more anabolic. You’re generating free radicals. 

You’re lowering insulin sensitivity, you’re increasing insulin resistance. You’re storing fat. Those fields of inflammation coming out of the fat stores is turning up. You’re more likely to shift into senescence. And one of those P53 cells, they go that. And so these things that are more bad for you, are activated when they’re acidulate, and deactivated when they’re deacidulated. So you’re either you’re net deacidulated, all the metabolism’s running really clean. But your net acidulated, you turn off the clean and you run dirty metabolism. And that’s really to like bulk up and store fat before the winter. It’s like, we’re hear more and more about uric acid as this fundamental switch between AMPK, is to starting you down that. I always say, AMPK starts the clean burn and sirtuins codify it into the system. So when that shut down, you go over this AMPD side, which is generating endogenous fructose, activating xanthine oxidase, creating uric acid, which is a net corrosive on the body, which turns up oxidative stress, turns down insulin sensitivity and makes you gain weight. That’s the whole how fructose does all this stuff. 

And that uric acid is a switch is becoming a really big thing. In fact, tomorrow I’m hosting Rick Johnson. I don’t know if he’s heard him on Peter Attia’s podcast. But he’s out here Colorado, and he focuses on that. Perlmutter just picked up this whole uric acid thing, and he’s doing that, and he learned a lot of this from Johnson. Johnson’s MD, urologists guy at Anschutz Medical Center. But you see there’s these sides to the metabolism and you wanna stay over on this clean side. There’s times where you wanna build up. And frankly, after I go do stem cells and stuff, I’ll let myself… I’ll eat more carbs, become more anabolic, I’ll put a little growth, flush on, and then I’ll flip over and try to clean everything back up.

Matthew Cook, M.D.

So then I think that this is super interesting, that this whole uric acid, and I’ve been following this. Talk me through sort of your philosophy or strategy on how we can use sort of a supplement strategy to manage uric acid?

Christopher Shade, PhD

So, it’s gonna come down to a lot of these things that are doing a lot of other work for us. Like quercetin seems to be in the center of the hub here. So it’s a uric acid blocker, xanthine oxidase blocker. Some things like it, like luteolin. Now those are in the products for the liver, they’re in the products for the AMPK, they’re in the NAD product, so we’ve got it all going on. Now, I’m gonna work with Rick to figure out the best nutraceuticals, and he’ll be able to take some of these products into clinic. And I’m gonna help him with some of his pharmaceutical for delivery systems for him. So I think we’ll come out with a lot more information in the next couple months to year, on the specific products. And I think what you’ll see is a specific product for blocking uric acid. ‘Cause uric acid if it starts building up, blocks of AMPK. So that’s supposed to be a feedback loop where it just keeps you going that way because the ice age is coming, the sun’s zooming in, and you better get fat now before that all happens. 

And so it’s just, we’re just meant to go that way. And so, one of the things that make uric acid, so of course fructose does. But what makes endogenous fructose acid? Anything that dehydrates you. So high salt diet without drinking a lot of water does it. Alcohol without enough water, too much alcohol does it. The high meat diets, the piercings are in there that can make the uric acid, but it’s also the saltiness and stuff. So more vegetable base, more water is gonna shift you over to AMPK more nicely. And then, what are these different compounds? Now there’s compounds that shift you over there. I mentioned the Berberine, psilomelane, the resveratrol, pterostilbene, quercetin. But then we’re looking at some other less used polyphenols that can flip you over there. And there’s a lot of data in the literature. 

But yeah, you’re gonna become a little… When you’re trying to bring that down, you’re gonna become more vegan, you’re gonna fast more, you’re gonna drink more water, you’re gonna keep the salt down, keep the alcohol down, and you’ll be able to shift over easier. In fact, I want to kind of have a system where I got the uric acid blocker, we got cardiovascular support, we got AMPK activation. And then, you have a uric acid meter. These are all fingertips. Uric acid meter, a blood sugar meter, and a ketone meter. And really, you can be running all these things at once. It’d still be healthy, but you gotta make sure all there. If you’ve got no ketones, high sugar and high uric acid, you’re gonna be in trouble.

Matthew Cook, M.D.

Right, and so then, as you get these easy measurements, then it’s sort of like driving around in your car. You look, and there’s a monitor that says how much gas is in your tank.

Christopher Shade, PhD

Yeah, exactly.

Matthew Cook, M.D.

And so then when we’re driving around in the biology of our real life, we need to keep uric acid down. We need to keep blood sugar down. And they’re few- Hmm?

Christopher Shade, PhD

Ketones up.

Matthew Cook, M.D.

Ketones up. And then, with that in mind, then as you have strategies and Harry McElroy, who I think who I love, Is one of my doctors. And so then he’s vegan, but then we’re definitely from the tribe of, if you come to my house, I’m probably gonna cook you an elk steak.

Christopher Shade, PhD

Yes. As am I, as you know.

Matthew Cook, M.D.

But so then… And it’s been an interesting evolution for me because I do intermittent fasting every day. I do either just your binder drink in the sauna or I will do a little liver sauce or bitters.

Christopher Shade, PhD

Yep.

Matthew Cook, M.D.

So I have some version of sort of push catch.

Christopher Shade, PhD

Yep.

Matthew Cook, M.D.

And then I’m doing those, some combination of intermittently facing through so that I can impact biology in those ways. And so then worry, I’m eating meat probably every day, but a small amount compared to before. Because basically what’s happened is I’ve noticed I’ve come into balance. And then as a strategy for people, I always have like an arugula salad and then a little steak. And five years ago, I would’ve needed to eat like a steak and a half. And now I just eat like, if I eat a steak, I’m totally full.

Christopher Shade, PhD

Yeah.

Matthew Cook, M.D.

Now- And so then finding a way to sort of come… And if you can get that cycle and exercise, that’s like 90% of the value.

Christopher Shade, PhD

Oh yeah, totally. And you’ll see, as your AMPK becomes more… It’s switching back and forth easier, you’re mobilizing your own resources. And you’re not like dependent on these cycles and needing the food all the time. And yeah, so we end up eating a little less. And the more we can go to these wild and grass fed types of meats… James Randi oh, lo told me that… He was giving some ridiculous number of phytochemicals that’s in like wild elk or wild game. And so you getting a lot of these things in there that aren’t in the corn ray stuff.

Matthew Cook, M.D.

And, there’s a interesting. This has always been like a theory of mine around like the liver and NAD type of stuff. Is that, if your liver’s toxic, then it has a hard time basically managing blood sugar for you. And so then as a result, if you have any alcohol and alcohol starts to slow that down, you get super hungry.

Christopher Shade, PhD

Oh, yeah.

Matthew Cook, M.D.

And so you see a lot of people that will drink and then suddenly they’re eating like after breakfast.

Christopher Shade, PhD

Well, that’s also uric acid, ’cause uric acid stimulates foraging behavior.

Matthew Cook, M.D.

Right.

Christopher Shade, PhD

And the alcohol does that. And so, yeah, if I’m gone with guys too late and partying too much, all of a sudden, the munchies kick in the way they would for weed. And it’s like, it’s not an neurotransmitter and endocannabinoid thing, but I think that’s a uric acid thing.

Matthew Cook, M.D.

Interesting. So then uric acid… And then that also is another thing. Like, I love that you said that the quercetin is at the hub of all of this stuff.

Christopher Shade, PhD

Yeah.

Matthew Cook, M.D.

It’s kind of it, then it’s helpful from an immune perspective for COVID also.

Christopher Shade, PhD

Yeah, and it was huge. There was data on it blocking ace two docking, that was from Oak Ridge Labs, quercetin and luteolin and both. They’re kind of like brothers. And then just all these things kept coming up of all these different ways. And from an immune perspective, AMPK that autophagy that tucking like a mitochondria into an autophagosome and breaking it down, you also do xenophagy. With viruses, bacteria, parasites, where you put them in an autophagosome and you break em down into parts and then you make antibodies to them. So it’s part of this higher level immune response. That second phase that kicks in, and when it kicks in, well, it contains and takes care of stuff and prevents the runaway inflammation from happening. And if that’s not happening, you probably won’t kill the bug. And the inflammasome lack of control takes off.

Matthew Cook, M.D.

Hmm, yeah. Now on the NAD front, I’ve historically done a lot of NAD IV.

Christopher Shade, PhD

You’ve what?

Matthew Cook, M.D.

Historically used NAD on intravenous basis in our practice. And that started early on because we were taking care of a lot of people for addiction. And so you see these, people had been drinking a bottle of vodka. And so then, it would be like there was NAD left in their body. ‘Cause NAD, one of the other things that it does is facilitates alcohol dehydrogenous. But as I’ve gone in our practice, I would say my philosophy of IVs in NAD is an analogous to your philosophy of what you’re talking about. And then for all of those people what I found is, I put them on a strategy basically what you’ve outlined. And that starts to harmoniously balance things over the arc of time. And when I do NAD IVs, a lot of times I just do a hundred milligrams now. And I’m doing vitamin C, and I’m doing glutathione, and I’m doing quercetin. And so then that becomes this kind of like stabilizing, balancing thing. And then we’ll do a little bit of NAD if we’re working on top of that, but not much. And then we’ll use some subcutaneous NAD. But I think I don’t even really like to do that, without doing everything that you’re doing to kind of work on the cycle and driving an optimal balance that way.

Christopher Shade, PhD

No, it’s really been nice. And this sort of day to day NAD building, you see the power comes up in the system, and it’s steady, and you can go off of it. And it takes a couple of weeks for the power to drain back out. And then you’re like, “Wait, what’s going on?” It’s like, “Oh, I went off the NAD.” And then it And you got all these other things working with it. And it’s just a real stable system there.

Matthew Cook, M.D.

But, then, I think this introduces people kind of to a 1.0 of a framework to think about this. Because that means there’s cycles that you’re driving, and they will achieve different things depending on what you’re working on. But then basically, almost every month you can be working kind of on a cycle or two. And then you’re working on detoxing, you’re working on autophagy, and you’re working on senescence.

Christopher Shade, PhD

Yep. 

Matthew Cook, M.D.

And working on Mitophagy, and then balancing these things. And now then everything that goes on top of that peptides, is gonna work orders of magnitude more effectively. Because then you’re driving physiological processes that are working.

Christopher Shade, PhD

Yeah exactly, you’re not trying to flip them over. So we have totally broken processes, let’s peptide them over. It’s like, “No, let’s fix them, make ’em stable.” And then let the peptides rise you up to that next level.

Matthew Cook, M.D.

How much in terms of a daily dose of NMN would you like to see someone on? And over the arc of a year, let’s say they’re cycling on and off. In terms of a milligram dose, what would be your optimal-

Christopher Shade, PhD

In our liposome systems, I like people on a hundred milligrams a day.

Matthew Cook, M.D.

Okay.

Christopher Shade, PhD

Which is NAD platinum that’s one teaspoon. If it’s NAD gold, that’s four pumps of that. Two to four pumps of the methyl charge. And that’s the one that I keep pretty stable. Because NAD needs don’t go away. You’re not stimula something like Nrf2, you’re just providing all the NAD you need for these other processes. And so then with the other things, I pulse more.

Matthew Cook, M.D.

Now, when people are listening to podcasts, one thing, people will talk about methylation. What is methylation?

Christopher Shade, PhD

It’s a good question. It’s one carbon transfers. But methylation… Something like SAMe is your big methyl donor. It’s turning on and off processes. Of course, there’s methylation of genes, where you’re turning on and off genes. And that’s controlled by NM methyl transferases. But these little on off switches are all over your biology. And so you need a robust bank of methyl groups, and a robust bank of S-adenosylmethionine to turn things on or off as is appropriate. It’s not all one way. ‘Cause generally in the methylation of the genome, they think, “Oh, we we’re methylating as we get older and turning things off.” And so there’s a fear that methyl B12 is gonna do that. But that’s controlled by different enzymes, how they do that. 

But SAMe is used all over the place for all kinds of things. And when you’re not supporting the regeneration of the methyl pools, then you build up homocystine and you go into a more cardio inflammatory situation. Mentally there tends to be depression, there’s high histamine activity. So the mass cells are less stable when there’s low methylation. So there’s various ways to look at my down, and foggy, and tired, probably more methyl groups. And homocystine is probably the best single measure of methylation activity. But if you take NMN or NR and you get a little bump and then it goes away or you’re not getting energy, you need more methylation.

Matthew Cook, M.D.

Right, so then this is something we’ll look at in terms of blood testing. So we look at that homocystine and we’re tracking to see how that is. Now I’m in the grab bag section of my questions. If you turn on podcasts these days, you cannot blink without hearing the word mass cell activation.

Christopher Shade, PhD

Yes.

Matthew Cook, M.D.

What is mass cell activation? How do you think about it? And then from a supplement perspective, are there some things that you that can help with that? Because I never heard of mass cell activation. Then I was at this ILADS meeting five years ago where they talked about it, now you cannot hear about it.

Christopher Shade, PhD

Mass cell activation syndrome, it’s a big thing. And so mass cells are those immune cells, very old, old immune cells that release histamines. And so antihistamines block those release of histamines. But these things are all through the body, including ones in the GI tract. They get stimulated by different antigens, and can release all kinds of different inflammatory cytokines. And that they release even before they degranulate and release the histamine. So we think about the red blotchiness and a runny nose as a histamine response or itchiness. But before that, there’s a lot of inflammatory cytokines that could come out of the mass cells, and they’ll create brain fog, fatigue, and it’ll often happen. One of the things where people miss it a lot is happening after they eat. And then they’re tired and foggy after they eat. 

And so there’s actually different muscles and different targets in the GI than there is systemic. So systemic, we have a product hista aid, which uses quercetin, luteolin, DIM and vitamin C, and acts really quickly. Like if your nose is going and you’re itchy, you take that, Ooh, calms it down really fast. Now it’s only in the blood for two hours. So you gotta, redose pretty often. And then, so there you need that bio availability in the GI. It’s more like using capsules. I will say, one of the things that I’ve found to be a use for people when they’re having a lot of this fatigue, and low energy and brain fog, especially after they eat, is OTC pharmaceutical Pepcid AC or Zantac famotidine. 

Targets GI histamine release, GI mass cells. And I found that was a great stabilizer for myself and for other people. Where I was like, I drink coffee and got foggy. And the methylation having methyl groups up helped, but this ended up being a really helpful thing. Especially when you’re trying to get people better and they have complex inflammatory syndromes. A lot of that can come from the mass cells. So, high methylation groups, great mass cell stability. Quercetin and luteolin are direct mass cell stabilizers. And then some of these OTC things, like famotidine from the Pepcid AC is intact, are real helpful with food intolerances.

Matthew Cook, M.D.

Okay, so then I love where this is going. And so then as you sort of think about all this stuff, the defining biggest problem that I think is more prevalent than anybody realizes is water damage buildings and mycotoxins and that whole side of the equation. And I know you’ve thought deeply about it. At a high level, how do you put that together and how do you think about getting rid of mycotoxins and kind of the entire environment?

Christopher Shade, PhD

Yeah, so mycotoxins mold damaged to people have just wildly active mass cells. So you’re always trying to create stability and get stuff out. So inflammation blocks detox, and so that’s a problem. And if everything you start to move out of you is blocking detox, then you really need a lot of stabilization while you’re doing the detox. So when you go into doing mold, getting mold out, yeah, push catch that whole thing. But extra inflammatory control. And so some extra hista aid, CBD and GABA are both very beneficial immune cells. Both mass cells and macrophages, have cannabinoid receptors and GABA receptors on them. 

And those can help turn down that reactivity. So for me if I start getting reactive to stuff, I take CBD, I might bake CBD AX. It’s our blend that has GABA, PharmaGABA and CBD in it. And I take the hista aid, and I take the methyl charge. And that tends to like really bring things under control. And then lots of binders alter throughout the day for mold. Even if you do two push catch cycles, take… We now have the binder in capsules, so it’s a little easier to take to work and throw some down. Take binder two other times during the day, lots of binder for mold and lots of inflammatory control.

Matthew Cook, M.D.

I heard you say earlier, and I liked that. How do you like combining the ultra binder with, I heard you say sometimes you’ll throw in a little bit of modified citrus pectin.

Christopher Shade, PhD

Yeah, actually the capsules have modified citrus pectin. I think both powder doesn’t yet. But you put a half teaspoon of modified citrus pectin in there with it, and then that’s got more of this inflammatory control. Remember inflammation blocks detox. So I like that one. Magnesium, but people are constipated, they gotta be pooping. And so a magnesium oxide like Oxy-Mag, these ones that aren’t absorbed that are just sucking water down into the GI tract. That can be blended in with that too.

Matthew Cook, M.D.

And then final question. The other big problem that lasts well, maybe too… You’ll have a lot of people and with long COVID, you start to look underneath and you go, “Oh, they found out they got tick born illness, that’s lie in them. Really Bartonella. what are your favorite strategies for dealing with those things?

Christopher Shade, PhD

Yeah, so one, in long COVID or CBD synergy, PM was the most effective thing for the constant inflammatory thing that was going on. And that seemed CBD, with curcumin and Boswellia, and beta caryophyllene, those are capsules that turned into nano particles. But then, if there’s infection under there, so a lot of people I’ve heard of and seen a lot of Epstein Barr and cytomegalovirus unregulated, post COVID. So in our world there, I use Cat’s Claw Elite, and that’s really good. It just sort of gets your immune system back on the right page with the cytomegalovirus or the Epstein Barr, so we can suppress it and control it naturally. And that’s the kind of thing. If you take that and you feel better right away, it was viral. If you feel worse, then you’ve got lime. So the Cats Claw Elite, Biocidin LSF, and microbe manager, microbe managers are capsules of artemisinin with some curcumin, and CBD, and quercetin, and silymarin, and I’ll kind rotate those. 

And people they tend to get this whole bio film thing up. And you’re not sure is that tick borne, is it… Fry Labs is good at starting to identify some of these bio films you had good standing for them. I know that was my problem, late viruses and bio films. The lime never really came back as a big hit for me. But taking these things steadily and rotating them, making sure you have enough binder on board in the beginning, making sure you’ve got some bitters and liver stuff. So I’ll set up push catches. And maybe it’s push catch with Cats Claw. Maybe I’m using micromanager as the push, because it’s a very strong bitter. Maybe I’m using it with liver sauce. How am I cycling in the Biocidin? But you just gonna come up with your strategy for it.

Matthew Cook, M.D.

Right, and so then for people to hear this, so then these push catch type of ideas which are kind of liver detox and detox strategies overall, managing AMPK, managing Nrf2. And so we kind of went through those strategies. Thinking about kind of inspections that may be on top up of that. But those are homeostatic things that we have to be doing at this baseline just to get our ability to detox. Because if we’re gonna go fight infections, we gotta that on.

Christopher Shade, PhD

The infection’s blocking detox, the toxins are blocking the immune system. You need to unravel all that shit. You gotta turn up your own stuff while you go, and you nail a bunch of those fuckers and then you get back on top. Eventually and get control back over the situation.

Matthew Cook, M.D.

And so then in terms of long COVID overall thoughts, what have been your kind of high level insights over the last-

Christopher Shade, PhD

Well, I’ll give you one that was surprising. Is estrogen’s ability to tamp down the circulatory inflammation. And I saw this with myself when my house burned down, so did my anastrozole. And the Arimidex… I wasn’t like decimated long COVID, but there was this inflammatory process going on. And when my estrogen levels back went up, that brought that away. And my friend Mindy, who does education here, we had her on a more antigenic hormone run, and her estrogen was a little low post-menopause. And then we did this topical estrogen that got her estrogen up higher, and that ended all her stuff. Like coughing and it just clearly like you go work out and you’re like, “Ouh it’s burning in there.” So, estrogen is very cardioprotective. And there was a big move to like suppress everybody’s estrogen pretty heavily, but we might have gone a little too far with that. So that was intriguing. The other stuff we saw was the long term CBD to control the inflammation while we go in there. Make sure to detox hard and use a lot of that Cats Claw to get residual stuff out. But the hormone one, that was a surpriser.

Matthew Cook, M.D.

Okay, I love it. I think that this is a extremely useful framework for sort of how to think about things. And I’m regarding this as sort of a one of hopefully infinite conversations that I have with you. And so,

Christopher Shade, PhD

Yes,

Matthew Cook, M.D.

this is a framework is then gonna be something that we’re gonna build on. And so then I’m gonna start kind of to… Then in our next call to kind of go through each of these strategies and say, “Okay, now once we’ve done that, okay, then this is what we would do with peptides.” This might be what we would do with stem cells. This is to… And then thinking about cycles of then regulating these processes over time.

Christopher Shade, PhD

Absolutely. Yep, when you’re running exosomes in, how do you deal with stem cells? Let it’s clean up before we do this. Where do the peptides go? Yeah, that’s what we gotta do.

Matthew Cook, M.D.

Okay, you’re my hero. I’m so grateful that you exist, because you’re helping the world and helping me. So thank you for everything.

Christopher Shade, PhD

Thanks so much, Matt, it’s been a great talk.