Reverse Biological Aging with Dr. Christopher Shade: Rational Wellness Podcast 255

Dr. Christopher Shade discusses How to Reverse Biological Aging with Dr. Ben Weitz.

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Podcast Highlights

3:05  Dr. Shade said that his chronological age is 53, but his biological age is younger. This is now measured by looking at methylation patterns on CPG islands in your DNA. This is through epigenetic clocks, such as the Horvath clock, as found in the Tru-Age test from Tru-Diagnostics.  [Turning Back Time with Epigenetic Clocks.]  The clocks have been trained or correlated with IQ, grip strength, balance, facial aging, etc.  If you are aging at a rapid rate, if you have a faster loss of function, then your biological age might be 70 when you’re 53, or if the pace of your aging is slow, then your biological age might be 43.  Our goal is to reduce our biological age to extend our health span.

6:35  Dr. Shade and Quicksilver Scientific have conducted a study using their supplements for three months and measuring their biological clock using TruDiagnostic’s TruAge test and the preliminary results look very good.  They saw improvement in the Horvath clock and in the pace of aging.  They beat the results of a two month caloric restriction trial.  They also saw positive epigenetic changes in certain white blood cells–monocytes and natural killer cells. The first month was detox with support for Nrf2 and AMPK activity (70% Nrf2/30% AMPK).  Second month, they shifted to 70% AMPK, 30% Nrf2, and a lot NAD+ and membrane building and sirtuin activation.   So clear things out, detox, then build up metabolic strength. Then the last month, we kept going on that mitochondrial metabolic strength, and the results were very positive.  According to Chris, “you start with AMPK phosphorylation with this PGC1A promoter for mitochondrial biogenesis, but then you have to deacetylate it with sirtuins, which means you have to have enough NAD+ to do that, and then you get full activation mitochondrial biogenesis, which makes more mitochondria per cell.”

11:14  AMPK, Nrf2.  How to slow the aging process should start with AMPK activation and this often goes hand in hand with Nrf2. Nrf2 is a master switch for chemo protection and when it’s upregulated, it’s called a nuclear transcription factor which means that it’s outside the nucleus and something triggers it to go into the nucleus.  Nrf2 is part of the chemo protection family, which includes antioxidants, detoxification, protein regulation, getting rid of unfolded proteins, fixing damaged proteins, and this is all cleanup stuff.  For example, to get rid of heavy metals, you need to raise nrf2 to bring up the glutathione genes and get rid of toxins like heavy metals.  AMPK can be triggered by fasting, carb restriction, exercise, and various nutraceuticals and pharmaceuticals such as metformin, berberine, resveratrol, and quercetin.  Fasting and carb restriction triggers you to mobilize and efficiently use your own stored energy resources, like glycogen, old proteins, and stored fat.  You use old proteins through autophagy.  You can increase glucose transporters, and lower insulin resistance/increase insulin sensitivity.  You are also going to mobilize stored fat and turn it into ketones for energy.  You can burn the fat out of fatty liver, which is called lipophagy.  If you take old, damaged mitochondria, and recycle them, this is mitophagy.  If you use old golgi apparatus and old endoplasmic reticulum, this is endoreticulophagy.  It’s the inner detoxification for your broken inner parts. So Nrf2 is more taking away environmental toxins and AMPK is more clearing out your own accumulations of waste, and that also includes unfolded proteins.  When you are always building proteins, sometimes you don’t make them right all the time, and you store the ones made improperly in vacuoles.  Eventually, if you don’t get rid of them, then your cells fill up with garbage.  So Nrf2 is an environmental cleanup and AMPK is a biological cleanup, and this raises yourself up to a higher metabolic efficiency. 

16:30  This autophagy happens because the body senses there are not enough amino acids to make up the proteins the body needs. There is also a switch that is engaged with this, called mTOR, the mammalian target of rapamycin.  Rapamycin was the first cancer drug that might be good for you because it blocks mTOR.  mTOR has a forward direction that is pro-growth and anabolic and then it is blocked and it causes you to go inward and recycle your own amino acids and burn your fat. If you are in growth mode all the time, you’re prone to cardiovascular disease and cancer.  Insulin and branch chain amino acids drive the pro-growth signals, while keto and intermittent fasting and the nutrients in the AMPK Charge product that Quicksilver produces and metformin all drive AMPK.

20:02  Uric acid.  There is a primal switch when your ATP (cellular energy) gets low, you can either go down the AMPK route or the AMPD route.  AMPK goes in and mobilizes resources, cleans up, and gives you insulin sensitivity, while AMPD does the opposite. AMPD increases fat storage, it further breaks down ATP. You burn off the AMP into xanthene, and then xanthene oxidase turns into uric acid.  Uric acid comes back around and blocks AMPK and keeps you stuck on the AMPD pathway. This AMPD pathway generates more uric acid, which creates creating mitochondrial stress and free radical damage inside the mitochondria, and it’s heavily associated with cardiovascular disease and early onset dementia.  If you are eating high fat but not restricting carbs enough, then you might need more polyphenols, more vegetables, you might not be eating enough vegetables, you might be eating too much salt, having too much alcohol, or not drinking enough water. 

22:40  Does promoting AMPK reduce cancer risk or protect cancer cells?  The reality is that while promoting AMPK and the other longevity pathways can prevent cancer, if cancer is present, they can also protect cancer cells.  But this is no reason not to promote the longevity pathways.

25:21  AMPK.  The best ways to stimulate AMPK is through intermittent fasting and also by working out fasted.  Almost every plant chemical has AMPK activation activity, including adaptogens and spices. The really strong ones include Berberine, Resveratrol and Quercetin.  Quercetin is so multifaceted because it stimulates AMPK, Nrf2, and sirtuins and is also a senolytic.  Milk thistle is both a AMPK and a sirtuin activator of the liver.  Many of the products that have AMPK activity also stimulate the sirtuins.  Ben Greenfield says that HIT training is the best way to activate AMPK with alternating periods for 30 seconds of all out training alternated with periods of rest. Morning is naturally more AMPK than night is. You have already fasted over night and there tends to be more autophagy in the morning and more rebuilding at night while sleeping.

29:35  NAD+.  NAD+ is a signaling molecule that’s present in the body for energy production, cellular energy, and for DNA repair.  At it’s most basic level, it’s going back and forth between NAD+, the oxidized form, and NADH, the reduced form. NAD+ is taking the electrons from your carbs, becoming NADH and going into the electron transport chain and dropping the electrons into the high energy electron transport chain and leaving the proton there. That’s eventually going to be pumped across the membrane, form that proton gradient, and come back through ATP synthase, and drive ATP formation.  So it’s shuttling energy from the sun, which is what built your carbs and your lipids, and bringing it in to make ATP.  NAD+ is also a cofactor in sirtuins, which are deacetylases. Acetyl groups are turning on or off different proteins.  To turn on the good anti-aging things, you deacetylate them, and turn on the bad anti-aging things, you acetylate them. But why would you want to acetylate the bad anti-aging things?  It’s to stop cancer growth.  While substances like resveratrol and pterostilbene and quercetin are sirtuin activators, NAD is the initial activator and it fits right into this hole in the sirtuin and activates it. NAD is also essential for gene repair. As we age, we’re always having assaults on our genes from getting exposed to toxins and radiation, etc.  PARPs go in to fix the genes, but they use the energy of NAD in this repair.  There’s also CD38, which also known as cyclic ADP ribose hydrolase, which seals up tight junctions when you get leaky gut or leaky brain or leaky liver, and this sucks in NAD as well.  NAD is doing all these things in every organ and therefore NAD deficiencies can play a role in eye disease, in fatty liver disease, in heart disease, etc. The way to promote NAD is to take one of the precursors like nicotinamide riboside or NMN.  Ideally you might want to take both of these, but because different companies hold the license to each of these, it would be too expensive to put both into a product. 

NAD originally comes from niacin, vitamin B3.  This is the story of the B vitamins. And then there’s the decrepit, degenerate, benign folic acid that everybody hates.  And then there’s the glorious 5-methyltetrahydrofolic, and then some of these half losers in between like folinic acid.  So it’s the same game.  B3 works its way up to NR and then to NMN and finally to the glory of NAD.  If NAD runs everything in the body, what can you do if you are a hunter gatherer and you don’t eat any food with niacin in it?  You can make niacin from tryptophan.  If you can’t eat any tryptophan, then you can recycle some of your cells, spit out some tryptophan and make it that way. It just takes longer and it takes more energy.  The enzymes that facilitate the jump up to NMN can get knocked out by inflammation and by age, so taking NMN and NR are the best ways to boost your NAD.  But there is also a balance with methylation. After the high phosphate bonds in NAD are broken down, you are left with nicotinamide, which is the non-flushing niacin, which blocks your sirtuins. You need SAM-e to methylate nicotinamide. If you deplete your SAM-e, this creates SAH, which creates Homocysteine, which gives you cardiovascular disease, inflammation, and depression.  So if you want to support NAD production, you also need to take B2, B12 and TMG to stimulate methionine regeneration.

42:36  Sirtuins.  Resveratrol and pterostilbene are both good products to stimulate the sirtuins. Quercetin and fisetin can also stimulate sirtuins and fisetin is also a senolytic.  When David Sinclair originally tried to promote longevity just with resveratrol, it didn’t work because you also need NAD activation or you will get mitochondrial dysfunction and then you also need enough methylation factors as well.

48:33  Senolytics and senescent cells.  A senescent cell is one that has suffered a toxic insult or mitochondrial dysfunction that causes telomere attrition.  Then the mitochondria start releasing pro-inflammatory mediators that diffuse out through the cell and cause growth cycle arrest.  The cell stops reproducing and it just sits there, becoming a zombie cell and it releases pro-inflammatory mediators.  That’s one of the major causes of the propagation of all that inflammation that shrivels us up and makes us old and decrepit.  There are two ways to get rid of these cells. You can reverse them and put them back into growth again and have them repair their mitochondria by having good Nrf2 and AMPK activity that restores the milieu inside the cell and restores the redox potential.  The other way is to get rid of these cells with senolytics, such as with quercetin, fisetin, resveratrol, pterostilbene, or curcumin.  Measuring senolytic activity is a challenge because when you go in and start cutting up these cells, there is a burst of senolytic cytokines, so it looks like there are more senescent cells rather than less and it takes a while to show a decrease.  We can show that senolytics can reverse phenotypic aging, but we can’t measure a decrease in sensecent cells as of yet.

52:38  Spermidine.  This was first isolated from sperm, but now can be derived from wheat germ and other vegetable products. It has a lot of activity for autophagy and mitophagy and senolytic activity.

53:45  Dosages.  Quicksilver products are in a liposomal form, which increases absorption, but they often include much lower dosages of these longevity products than the studies show are effective. So how do we know that we will be getting the proper dosages in these products. Chris explained that their quercetin product has a 25 fold increase in absorption, so 20 gm is equivalent to 500 mg.  Because their BioAge Reversal study, which has yet to be published, showed that using their products for three months was able to reverse the biological aging process, so the dosages used must be effective.



Dr. Christopher Shade is the founder and CEO of Quicksilver Scientific, which has revolutionized the nutritional supplement industry with their innovative nanoparticles and liposomal delivery system, their heavy metal testing, and their detoxification protocols that have become the standard for many for reducing heavy metals and mycotoxins.  Quicksilver also offers a great suite of age optimization products, including metabolic activators, NAD+, and adaptogenic blends, as well as hormone support.

Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss and also athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations.


Podcast Transcript

Dr. Weitz:            Hey, this is Dr. Ben Weitz, host of the Rational Wellness podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting edge health information. Subscribe to the Rational Wellness podcast for weekly updates, and to learn more, check out my website, drweitz.com. Thanks for joining me, and let’s jump into the podcast.

Hello, Rational Wellness podcasters. Very exciting today to be talking to one of my favorite guests, Dr. Christopher Shade. Today, we’ll be speaking about longevity. We will be speak about how to delay the aging process to reduce the likelihood of chronic diseases and how to live longer and better, how do we take that aging curve where we see that aging for many is this long slow decline in function and increasing onset of chronic diseases that starts in our 30s and 40s, and turn it into a big rectangle where we maintain a strong level of function for a long period of time, and then quickly drop off.

Today, we’ll be talking about some of the key metabolic pathways and processes that have been identified to play a big role in aging, including AMPK, Nrf2, sirtuins, NAD+, senolytics, as well as hormones and toxins. I recently heard David Sinclair, famed longevity researcher saying on his podcast that these longevity survival pathways are like the Pentagon, which is where the coordinated defense of our country is organized, and we’re trying to make a crank call to the Pentagon for them to send out the troops to defend the body even though there’s no immediate threat. That’s what we’re doing when we are taking nutraceuticals, using drugs off label like metformin, peptides, practice intermittent fasting, cryotherapy in order to stimulate these longevity pathways.

Dr. Christopher Shade is the founder and CEO of Quicksilver Scientific, which has revolutionized the nutritional supplemented in industry with their innovative nanoparticles and liposomal delivery system. They’re a heavy metal testing and they’re detoxification protocols that have become the standard for many for reducing heavy metals and mycotoxins. Quicksilver now offers a new longevity line. I also want to say that after listening to this podcast, you can get 15% off your next order of products from Quicksilver Scientific by using the affiliate code WEITZ15. Chris, thank you so much for joining me again today.

Dr. Shade:           Great to be here, Ben.

Dr. Weitz:            Good. So before we get into what we can do to live longer, what do you think is the … Let’s talk about what’s the difference between chronological age and biological age, and then what’s the best way to measure this.

Dr. Shade:           Yeah. So chronological age, we all know I am 53 right now, but what’s my biological age? There’s a lot of ways that they go about measuring it. For a while, they were looking at different blood markers, and then what’s grown to be the norm is looking at methylation patterns on something called CPG islands in your DNA. So these epigenetic clocks like the original Horvath clock have been used extensively, and it’s funny, they say that they train the clock with people at a certain age more or less function.  So they’re taking people and they’re relating IQ, grip strength, balance, facial aging, IQ all to biological age versus the chronological age. There’s also a new clock. So in fact, as we talk, we’ll talk about a 40-person study where we put them through the paces of one of our systems to detoxify, raise AMPK, raise mitochondrial strength, and we’re able to shift back the biological age in this cohort.

Also, there’s a new one called the DunedinPACE.  Who names these things? Dunedin, if you’re from New Zealand, you’d be like, “Well, yeah, that’s called Miami Beach.” Dunedin is this little beach town at the south of New Zealand. They don’t make Miami beaches there. They make Dunedins.  So they had calibrated this clock. It was between Duke and these guys at the University of Otago and one other place, maybe Oxford. What they did is they worked on the pace of aging. So it’s more of an instantaneous measurement of the pace of your aging, how fast these genes are shutting down over time. So time is this progressive loss of function, and if the loss of function happens faster than the chronological years, then you’re aging at a rapid rate. So your biological age may be 70 when you’re 53.  When the pace of aging is slow, then over the period of time of having a slow pace of aging, then you get to 53 and your biological age is 43 or one of my friends at one of my doctors who prescribes for me, she’s 54 and she registered a 30.

Dr. Weitz:            Really? Wow.

Dr. Shade:           She uses everything. Yeah. So there’s these measures, and what we’re trying to do is extend our health span. You brought it up, run as fast as you can and then quickly. Remember the Blues Brothers? It’s the Blues, and it just drives like mad, and it’s cruising down the highway and the cops are all crashing trying to catch it. It gets to the final courthouse where it’s supposed to stop. They closed the doors and it just falls into a pile of bolts and it’s all over. So that’s what I want it to be, and that’s what we try to have is to have a good health span.

Dr. Weitz:            Right. Exactly. Yeah. So have the results of that study that you did with the biological clock, the study’s been completed?

Dr. Shade:           Yeah. It’s been completed. We got the analysis back. We’re using TruDiagnostic, which is the go-to out there now.

Dr. Weitz:            Right. Yeah. I think I talked to Ryan Smith. He mentioned that you guys were doing a study.

Dr. Shade:           Yeah, yeah. So we finished that all up and the results were great. We got very significant changes in the Horvath clock. We had very significant changes in the pace of aging. We, actually, in three months there, we beat the results from the calorie trial, which was a two month caloric restriction trial. That’s the only thing shown to slow the pace of aging. They pulled back 25% on their calories for two years. They changed the rate of aging, but they didn’t change the absolute clock.  Then looking into subsets, we found really strong changes in immune, and when you’re looking at the genes that were differentially hypomethylated or hypermethylated, a number of these were related to immune cells. So there’s a significant change epigenetically in the monocytes, in the natural killer cells, and what was the other one?  I got it here on the screen behind me.  Coming on now. There it is. B cells. Yeah. Natural killer B cells were the most significant, and then monocytes after that.  So it was really exciting. It was a three-month program. The first month was a detox, but with AMPK activity to it, say 70% Nrf2, 30% AMPK. Second month, we shift to 70% AMPK, 30% Nrf2, and a lot NAD building and membrane buildings, sirtuin activation, getting the mitochondria really clear. So clear things out, detox, then build up metabolic strength. Then the last month, we kept going on that mitochondrial metabolic strength, and we got these great results. As we talk about this more, we’re going to see some of these things are hard to uncouple like Nrf2 and the AMPK. You think they’re separate, but they’re so coregulated.

Then AMPK and sirtuins.  Well, one is just a secondary level of the other.  A lot of this metabolic clarity, I like to call it cardiometabolic efficiency, begins at AMPK. Then if you have enough NAD, you encode that into sirtuins secondarily.  So like mitochondrial biogenesis, you start with AMPK phosphorylation with this PGC1A promoter for mitochondrial biogenesis, but then you have to deacetylate it with sirtuins, which means you have to have enough NAD to do that, and then you get full activation mitochondrial biogenesis, which makes more mitochondria per cell.  So there are almost like these interwoven progressive layers of encoding this higher level metabolism.

Dr. Weitz:            That’s interesting. You mentioned about the immune system function and that’s definitely one of the markers of aging is when we age, the immune system tends to have less and less function, which is why you see-

Dr. Shade:           Senescence.

Dr. Weitz:            Exactly. So I read the Fahy trial in which it was the first trial that they were able to reverse aging, and they also looked at something called thymus involution, which means shrinking of the thymus gland, and they were able to reverse that, and have it as an indicator that the immune system is actually getting stronger rather than weaker, and that’s super important. In fact, we just recently saw what happened during the pandemic to seniors who have a weaker immune system. They weren’t able to fight off the virus as well.

Dr. Shade:           Yup. Yeah. They were really wiped out and it was like, “I wish I could have done some of that thymus work.” I mean, they were imaging them and stuff. We weren’t really set for that, but I’d love to go in deeper and reproduce some of these things, get better blood markers. One of the things we tried to do is get some of the blood markers, but it’s so nascent right now.

Dr. Weitz:            You know what? You should talk to Vojdani about doing a lymphocyte map test because that’s the first test that actually maps out all the specific T cells.

Dr. Shade:           Oh, so Ari has that.

Dr. Weitz:            Yeah. Yes. He just came out with it.

Dr. Shade:           Oh, jeez! That would be great. I’m going to give him a call.

Dr. Weitz:            Yeah, yeah, yeah. So let’s get right to what do we need to do to slow the aging process and live longer. Why don’t we start maybe with AMPK?

Dr. Shade:           Yeah. Well, we have this conceptualization of it that we call the longevity wheel, and it looks like a Star of David. It’s a six point wheel, and it’s got pop, pop, pop, pop, pop, pop, and these are things that you can intervene in. The top spoke of the wheel is AMPK, Nrf2. That’s what we’re going to talk about. Just to fill in, then then the next spoke is NAD. Plus, the next is sirtuins. The next is telomeres. The next is senolytics or senescent cells, and then the neuroendocrine system.  Why is Nrf2 and AMPK at the top, and what are the two, and why do they go together? So Nrf2 we’ve talked about a lot. You and I have talked about it’s this master switch for chemo protection, which when it’s upregulated, well, first it’s called a nuclear transcription factor, and that means that it’s outside the nucleus, and something triggers it to go into the nucleus. Sometimes they just hit signalers on the wall of the nucleus that go in, but the signal gets in and it stimulates transcription or upregulation of genes that go with some family.  For Nrf2, that family is the chemo protection family. So it’s antioxidants, detoxification, protein regulation, getting rid of unfolded proteins, fixing damaged proteins. It’s all cleanup stuff, and that’s Nrf2. We always talked about that because that was always metal detox guy. So you got to raise Nrf2 to bring up all the glutathione genes and get rid of toxins like heavy metals.

Then we did a study or actually [inaudible 00:13:10] down in Houston. He’s a functional medicine doc, did study on our PushCatch liver detox system where he found 82% resolution of fatty liver in one to two months. Just really crazy. We’re like, “Wow! You move toxins out and it does that?”  “Well, no, not exactly. That’s part of moving toxins out, but even if you move all the toxins out at once, that wouldn’t totally happen.”

AMPK then is this trigger, the AMP-kinase, and it’s triggered by certain things like running out of energy, and that would be fasting, carb restriction, exercise, and it also can be triggered by a bunch of nutraceuticals and pharmaceuticals such as metformin, berberine, resveratrol, quercetin. So when you trigger this, now remember, fasting, carb restriction, it triggers you to mobilize and efficiently use your own stored energy resources. So you’re going to mobilize glycogen. You can increase actually glucose transporters, and you’re going to lower insulin resistance, increase insulin sensitivity, and become a clean burning machine.  Then you’re going to reach into your fat. You’re going to mobilize fat. You’re going to turn it into ketones. This is how you go into ketosis and you’re going to use all that for clean energy. It’s why these fasting and exercise get rid of the symptoms of metabolic disease, and insulin resistance, things like that.  So AMPK is part and parcel of that cleaning up, but you’re going to your inner resources. You’re using your inner glycogens or sugar and fat. How are you going to use proteins? You get them through autophagy. So this is super, super important to both detoxification and longevity because what’s autophagy but self-eating. You’re going, you’re taking whole cells, you’re taking deposits. In fact, the burning of the fat out of the fatty liver is called lipophagy, so eating the stored lipids.  If you’re taking a old mitochondria that’s damaged, you do mitophagy. You could be breaking out of golgi apparatus and part of an endoplasmic reticulum. That’s endoreticulophagy, and you’re going to break all that down into its raw materials and you’re going to reuse it, and that includes amino acids and fatty acids, nucleic acids even if you’re taking whole cells. So it’s a recycling system. It’s the inner detoxification for your broken inner parts. So Nrf2 is more taking away environmental toxins and AMPK is more clearing out your own accumulations of waste, and that also includes unfolded proteins.

When you’re making proteins all the time, you don’t make them right all the time. And you store the ones that aren’t properly made in these vacuoles, and eventually, if you don’t get rid of them, it’s like taking the trash out of your house. Your house fills up with garbage. So Nrf2 is this environmental cleanup. AMPK is this biological cleanup, and this raising yourself up to a higher metabolic efficiency.

Dr. Weitz:            This happens because the body senses there aren’t enough amino acids around to make up the proteins they need. So that’s why the body starts recycling these other pieces of the cells.

Dr. Shade:           Yeah, essentially. Now, there’s this switch that’s intimately engaged in this, and this is mTOR, the mammalian target of rapamycin. So rapamycin was the first cancer drug that was ever really good for you because it would block this thing called mTOR. So mTOR has a forward direction and a blocked. The forward direction is anabolic and it’s pro-growth and it builds mass and it puts on mass, but we know if we just put on mass all the time, we’re going to get sloppy and messy and dirty. I mean, even weight lifters put on mass and then they cut it back down. All right?  So if you’re growing all the time, you’re prone to cardiovascular stuff and cancer and stuff. So you need a block to that. So when you block it, then you go inward and you recycle your own amino acids, you use your fats, you burn all that. So what drives it forward and what blocks it? So the things that drive it forward are insulin and branched-chain amino acids. The branched-chain amino acids are what goes back to you, sensing that you don’t have enough amino acids around and you start recycling old parts.

So when we’re eating carbs and protein all the time, we’re gaining mass. This is part of why keto was so therapeutic, where paleo, some people it worked and some people didn’t because they took in so much protein they didn’t get as much of the mTOR blocking, but then we have things like intermittent fasting. If we overlay some of these chemical triggers for it, maybe you’re using off-label metformin or maybe you’re using something like our product AMPK Charge or Keto Before 6, and even of our Liver Sauce, that’s why the Liver Sauce gets rid of the fatty liver so well.  Yeah, it was moving toxins and the Nrf2 upregulator, but the quercetin, the luteolin, the milk thistle, those were all strong upregulators of AMPK. So we can take these AMPK activators while we’re intermittent fasting and get this flush of activity. In fact, we used to call the product Keto Before 6 because you could be keto by day and they need carbs at night and then do it again the next day. So you’re getting some of both worlds.

Dr. Weitz:            You think about this argument because I was just talking to somebody about diabetes this morning and she was advocating for not eating a lot of fat because some of the data indicates that saturated fat reduces insulin sensitivity.

Dr. Shade:           I think it’s going to come down to what your blend of macros are, how much saturated, and are we talking about Crisco or are we talking about these beef tallow? Those are both saturated fats, and some are very strongly pro-inflammatory and some aren’t, and then there’s some other-

Dr. Weitz:            There’s a group of folks who are advocating, some of them are advocating a vegan diet, but they’re countering the lower carb diet, often advocated now for diabetics saying, “No, no. If you eat a higher fat diet, it impedes insulin sensitivity.”

Dr. Shade:           I think it’s going to come down to a couple of factors that they may not be looking at. Now, one of the subjects that’s coming up really hot and heavy right now is uric acid, and you’ll see Perlmutter is talking about. Rick Johnson is one of the masters of that. We’re going to have them here lecturing at our Colorado Functional Forum in April. I’m actually roping then into helping me prove out some of the products that we’re making for uric acid blocking.  So then this is going to bring our AMPK discussion back to this switch. You’ll see in Perlmutter’s book, Drop Acid, he talks about is this primal switch. When your ATP goes low, you can go one or two ways. You can go the AMPK route or the AMPD route. AMPK goes in and mobilizes resources, cleans up, and gives you insulin sensitivity. It gets rid resistance. AMPD goes exactly the opposite path. It’s made to get you fat. AMPK is taking off fat. AMPD is gaining fat. It’s breaking ATP down instead of regenerating it as in the AMPK pathway. You’re burning more energy to regenerate your ATP here. Here, you burn off the AMP into xanthene, and then xanthene oxidase turns into uric acid.  Uric acid comes back around and blocks AMPK and keeps you stuck on the AMPD pathway. Now, the AMPD pathway generating all this uric acid, the uric acid is creating mitochondrial stress and creating free radical damage inside the mitochondria, and it’s heavily associated with cardiovascular disease, and more importantly, early onset dementia.

So if you’re eating fat and other things that you’re doing like maybe you’re eating high fat but not restricting carb enough or you are prone to uric acid, maybe you need more polyphenols in your diet, you need more vegetables to block that path or you’re eating too much salt, you’re drinking too much alcohol, the biggest culprit is just not having enough water keeps you always down that path.  So the fat then is going to become inflammatory fat instead of clean burning fat, which is over here. So I think one of the things that I think I’m going to be advocating is that you got your uric acid meter, your keto meter, and your sugar meter, and you’re tuning yourself in so that you’re going down the AMPK side.

Dr. Weitz:            Interesting. I was going down the AMPK rabbit hole this weekend and I found one article that said that AMPK appears to reduce cancer risk by switching off cellular growth pathways, but if there is already cancer, the AMPK might be able to protect the cancer cells against stresses, such as shortage of oxygen or oxidative stress.

Dr. Shade:           Yeah. So is it going to protect against apoptosis? So it can keep you from going into apoptosis and maybe help the survival mechanism, but realize that it’s the biggest freaking trap in the world. Cancer and fear of cancer is the biggest impediment to health because every single thing that makes you live long makes cancer live long.  Now, just shut the damn argument down for a second, then bring it back and say, “What has cancer done that is genius? Cancer has immortalized itself. How does it immortalize itself? It upregulates glutathione. It upregulates NAD production. It upregulates growth hormone production. It controls AMPK and all these different pathways towards its longevity.  Then everybody’s like, “Well, what if I already have cancer? Then any of these things that help my longevity are going to help the longevity of my cancer.” Well, your cancer is going to show itself at some point and then you’re going to go after it, and it’s a certain way that you go after it, but having a healthy AMPK is going to prevent you from ever getting it in the first place. Then being afraid of doing these things that promote longevity, in case there’s some tumor somewhere in you, I don’t know, go get a big scan or something because it just becomes such a trap. Don’t you think?

Dr. Weitz:            Yeah. I’m sure. It’s also, I’m sure, the balance and the double edged sword of things that-

Dr. Shade:           Oh, hyaluronic acid, that’s another thing that cancer has a lot of. So all of a sudden, everything that immortalized cells have a lot of becomes a death trap. Yet, that’s all the stuff that makes you live longer. So yeah, that may be tactically true, but I mean, nobody is saying that when you’re taking berberine and quercetin and EGCD, I mean, there’s people using those as therapeutics for cancer. So I don’t think you’re in any risk of all of a sudden you’re going to go off the deep end.

Dr. Weitz:            So what’s the best way to stimulate the AMPK? What are the best strategies here?

Dr. Shade:           Yeah. So I love intermittent fasting. I think it’s a great thing. Some women it’s a little bit hard, but get as much fasting as you can, then workout fasted. Add in the AMPK activators. Now, here, as a broad brush, almost every plant chemical has AMPK activation activity to it, and including the adaptogens and all those plants that we love a lot of, spices-

Dr. Weitz:            We want to take the ones that are going to be most efficient and take the right dosage.

Dr. Shade:           Yeah, so some of the really strong ones, berberine, resveratrol, quercetin. Quercetin’s such a multicomponent for us and Nrf2, AMPK, sirtuins. It’s a senolytic. That’s a really, really good one. Then things like milk thistle. Part of that is AMPK and sirtuin activation of the liver. A lot of these things that are AMPK activators are also sirtuin activators.  So there’s this whole grouping of things that are really good for your metabolism. So you take those when you’re fasted or at least don’t have a lot of carb in you and maybe get some exercise in.  Ben Greenfield says the strongest AMPK activation are HIITs. He says 30 seconds as hard as you possibly can, and then I think he said four minutes of rest and then 30 seconds as hard as you possibly can, and then 30 minutes of rest, but anyway that you stack some use and exercise, lack of carbs and this and the AMPK activators together, you’re going to get a lot out of that.

Morning is naturally more AMPK than night is. We’ve just gone through the fasting, we’ve already got the fasting primed. Like in the skin, it’s more breaking down. It’s doing autophagy in the morning, and at night, you’re sleeping and it’s rebuilding everything. So I like to stack the AMPK activity into the morning and build up at night. So my carbs, those come at night and I intermittent the fast in the morning. Lunch, hopefully it’s salad and some protein and still low carb, but that varies a little bit depending on where I am. There’ll be times where I’m really cleaning up and then times maybe I just had stem cells or exosomes and I’m a little more anabolic, and then you’ll go more in.  I think understanding those two poles of the day, AM and PM are naturally that way a little bit, and then the pendulum of your life, “I’m trying to build a little bit, I’m trying to cut down and clean a little bit,” and I definitely go into times where I’m like, “Uh-oh. This baby is building up a little bit,” and then I really start fasting hard, and it cleans up really quick.

Dr. Weitz:            You just mentioned exosomes and stem cells. Have you gotten into those?

Dr. Shade:           Oh, yeah, yeah. I’ve gone offshore down to Columbia and done cord blood cells twice. I do exosomes every couple of months.

Dr. Weitz:            Which exosomes do you do?

Dr. Shade:           Which? I use Kimera. I mean, there’s not a lot of them out there. Kimera just shifted to doing only cosmetic. That window is closing a little bit in the FDA. So my freezer is filling up with them until there’s something else. There’s a lot of movement in peptides, too. Those are real good regenerative.

Dr. Weitz:            Sinclair was talking about he had some friends apparently who have a machine where they can manufacture their own peptides at their home.

Dr. Shade:           What? That’s crazy.

Dr. Weitz:            I don’t know. Probably very wealthy friends, but-

Dr. Shade:           Yes. Yes, very, very wealthy, “I have my peptide generator machine here. I got it used for $500,000 from Oxford University.”

Dr. Weitz:            So let’s talk about NAD+, which is this signaling molecule that’s present in the body for energy production, cellular energy, DNA repair.

Dr. Shade:           Yeah. So NAD is awesome, and it’s just the multiple levels at which it works are just crazy. There’s so many levels that are even understandable, but at its most basic level, it’s going back and forth between NAD+, the oxidized form, and NADH, the reduced form. It’s doing that by oxidizing your inputs of energy. That would be carbs and lipids. It’s taking the electrons away from them as your carbs make their way off to CO2 and at each little part of the citric acid cycle, all these different breakdowns. It’s NAD+. It’s taking to electrons, becoming NADH, and then it’s going into the electron transport chain, and it’s dropping the electrons into the high energy electron transport chain and leaving the proton there. That’s eventually going to be pumped across the membrane, form that proton gradient, and come back through ATP synthase, and drive ATP formation.  So it’s shuttling energy from the sun, which is what built your carbs and your lipids and bringing it in to make ATP. All right? So if it just did that, it would be a great molecule, but it does so much else.

So then it’s also the co-factor in sirtuins. So sirtuins are deacetylases, and acetyl groups are turning on or off different protein, and there’s the good anti-aging things and to turn them on, you deacetylate them, and then the bad anti-aging things, and to turn them on, you acetylate them. So when the acetyl groups are on, the sirtuin or a lot of the anti-aging things like FOXOs are off and things like P53, which makes more senescence, and why would you even do this stuff? It’s to stop cancer growth.  So a lot of the slowing down and winding down of the body is to make sure that cancer doesn’t take off and get on a run. So the sirtuins are shifting you over this cleaner building through this deacetylase activity. So we think about things like resveratrol and pterostilbene and quercetin and sirtuin activators, but actually, NAD is the initial activator and it fits right into this hole in the sirtuin and activates it.

Then there’s another hole where the sirtuin activating compounds. You’ll see Sinclair call them STACs. They fit into another part in the molecule and hyperactivated, and get it super wound up. So NAD is essential for having these sirtuins go on, and then it’s also essential for gene repair. So as we get older, we’re having assaults on our genes all the time and, say I get exposed to some radiation and it damages a gene. There’s something called a PARP that’s going to go in and try to fix it, and it has to use the energy of NAD to fix.  So it’s sucking anything that damages your genes, sucks a ton of NAD in there. Now, what’s that going to do? It’s going to take the NAD away from the mitochondria so the mitochondria can’t complete the electron transport chain, and you’re lowering energy. It’s going to take things away from sirtuins, so then the sirtuins aren’t going to be deacetylating the good genes, and so it’s sucking all this repair over there.

There’s also CD38. One of the good things that they do is seal up tight junctions when you’re getting leaky gut or leaky blood-brain barrier or leaky liver. So that’s sucking NAD into that activity, too. So there’s this hole, and then there’s some other ones that I don’t to understand as much into how it’s deciding which genes are turned on and off, so this epigenetic regulation of the epigenome, what we can turn on and what we can turn off. It’s basically, do we have NAD despair?  We’re going to turn on the good. Do we not?  We’re going to just hold our own.  We’re going to hold the fort down and make sure we’re at just default functioning.  When we’re in default functioning too long, there’s a lot of theories of cancer emerging from in that default functioning, this explosion or this overgrowth.

So NAD is doing all these things throughout every organ, and you could relate NAD deficiencies to eye disease, liver disease. I mean, you waste out your NAD, fatty liver is the first thing that you get, heart disease, every different organ. So NAD is really, really a powerhouse for driving the whole body and then driving what are the expressions of your genome. Remember, this is the consciousness of the body is deciding. You have multiple pathways, multiple possibilities for your consciousness to choose from in your physiological outcomes. NAD is right in that decision tree of what’s possible and what’s not possible.

Dr. Weitz:            A way to promote NAD is to take one of the precursors like nicotinamide riboside or NMN, and there seems to be two camps and debates as to which one is more effective.

Dr. Shade:           Yeah. Well, that’s just basically because humans like to be on this camp or the other camp. You’re a freaking liberal or you’re a freaking conservative, and you’re demonized either way.  It’s just, “Oh, are you NR or NMN?”  Look, where did all this still come from?  It comes from Sinclair.  Then he’s loathed to hear this, but his advisor, Leonard Guarente and him had a little rift.  So Guarente is all about pterostilbene and NR and has MLM product doing that, and Sinclair is all about resveratrol and NMN and had some shit on that.  So they got this little war like, “Which one is better?”  They’re both good.  Really, you want both of them probably in a product, but you can never get a license to get both of them because there’s intellectual property around it.  So we have a liposome of NMN. I made a liposome for Crominex of NR. It was freaking great, but they didn’t want it. So I can’t do that, and so I just do the NMN, but in the liposome, it’s freaking great. So the camp thing is silly there, but let’s get back to how you build that NAD and where does NAD come from normally? So NAD, nicotinamide adenine dinucleotide.

Dr. Weitz:            Niacin.

Dr. Shade:           Right, right. So this is the high level of B3 and you look at it like the story of the B vitamins. There’s the decrepit, degenerate, benign folic acid. Everybody hates it. It does nothing but lay vape to the universe, and then there’s the glorious 5-methyltetrahydrofolic, and then some of these half losers in between like folinic acid. So it’s the same game. B3 works its way up to the glory of NAD, and right before that you’re NMN, and right before that you’re NR.  So that’s where all this sequences, but as we get all, it’s hard to take the degenerate vitamins and make them into the glory. You’re just not as good of it, but then you think, if NAD runs everything in your body, what are you going to do if you don’t have some food, you’re a hunter gatherer and there’s nothing with niacin in it?  Well, you can make it from the de novo pathway where you make it from tryptophan.  If you can’t eat any tryptophan, you just recycle some of your cells, spit out some tryptophan, and you take it through a bunch of pathways. It just takes longer.  It takes more energy.  The enzymes to get up that last jump, it’s actually the jump up to NMN is that one gets knocked out by inflammation, knocked out by being old.  Anything that makes you sick makes that doesn’t work.  So coming in with NMN and NR are the best ways to instantly get you up to that NAD.

Then what people always miss is the balance with methylation. So NAD, all right, great, it’s going to activate the sirtuin, killer. What’s formed from that? It breaks down and all those high phosphate bonds are broken, energy goes into the system, and you’re left with nicotinamide.  Remember, that’s the non-flushing niacin. Well, nicotinamide blocks sirtuins. So you can’t build up this pool and nicotinamide need to drive it back up into NAD, but if you’re having a hard time doing that, then you’re blocking all your sirtuins.  So you got this circle called the salvage pathway, and it’s going down here and getting stuck.  So what happens then?  You pee it out, but to pee it out, you have to make it into methylnicotinamide. Where do you get the methyl group?  SAM-e?  So SAM-e methylates nicotinamide, you pee it away. You come in with a fresh NMN or NR and you keep driving this cycle, but you’re bringing constant input out and leaving stuff out the back. In doing that, you’re depleting your SAM-e and creating SAH, which creates then homocysteine. So if you keep driving that, you’re going to build up homocysteine and deplete SAM-e. Then what does homocysteine do? That gives you cardiovascular disease and you have lower methylation, and then you’re depressed and you’re inflamed and all this shit. So then you got to stimulate both the methionine cycle, which is going to regenerate methionine from homocystine and that’s interlaced with the folate cycle.  So you want to stimulate MTHFR, which you do with B2, and you want to stimulate the methionine regeneration. So basically, your co-factors you need, you need B2, you need B12, and TMG, and the pauper’s pathway to get there is just lots of TMG.  So if you’re going to drive NR or NMN, you’ve got to support methylation so those two are balanced.


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Dr. Weitz:            It’s interesting that you were talking about acetylation, and there’s so much focus on epigenetics as being all about methylation. I wonder if we just haven’t gotten to the research on acetylation and some of these other pathways.

Dr. Shade:           That’s histone acetylation. So there’s methylation and histone acetylation. Those are the two main epigenetic factors, and that’s actually probably how NAD controls so much of the epigenome, but it’s the methylation over time is the thing that is constantly increasing, and that’s the thing that you can do the clock with. They don’t have a clock with histone acetylation, and so they just ignore it, and everything’s about methylation. We all can run to one side and some people are worried, “Oh, my God! If I take too much methylation supplements, I’m going to methylate all my genome.”  In Kara Fitzgerald’s work, she’s a little worried about that, but there’s all this balance, and that’s great. I’m glad that you pointed that out because why aren’t we talking about that side of the whole deal because you look up epigenetics, those are the two fundamental ways that you turn on and turn off different gene sets. It’s important sometimes to shut things off and sometimes to open them up, and you’ve got the balance and you’re allowing both sides and allowing the enzymes to control all that. Then everything’s going to be great.

Dr. Weitz:            So in terms of sirtuins, you just mentioned resveratrol, you mentioned pterostilbene, there’s something called fisetin. What do you think about some of those different ways of stimulating sirtuins?

Dr. Shade:           I think they’re all good as long as you’re feeding in enough NAD. So resveratrol versus pterostilbene, I think they’re fundamentally identical. Pterostilbene has better data going through the gut because it’s got better absorption, but at a cellular level, I don’t think it’s any better. We’re going with nanoemulsions. I don’t really think it matters. We have a product coming out with both of them in it. Till now, we’ve been using mostly resveratrol because pterostilbene was so overpriced, but now it got better so now we’re using both.  Quercetin, I guess fisetin does it, too, but fisetin is also a senolytic. So then we’re going to talk about senolytics as well, but there’s all these things raise sirtuin activity, but if you don’t have enough NAD, here’s where there’s some conflicting data about resveratrol. Resveratrol, they tried to make that into a drug and they ran into phase two trials where some people were getting screwed up by it. Now, they were taking massive doses and trying to drive everything with that. They weren’t even thinking about supporting NAD. So here’s what happens. So I said that-

Dr. Weitz:            By the way, is this where … I remember years ago Sinclair was this guy who his big thing was … We know that caloric restriction seems to have this longevity benefit, but who really wants to live like that, eating 30% or 40% of your calories less than you should, and then the worst tragedy would be live that way like Roy Walford did and suffer, and have this miserable life and then die of ALS in your 70s, anyway, but I remember-

Dr. Shade:           So we’re trying to get to … All right. So he’s like, “Well, then we’re just going to pump the resveratrol in,” because, yeah, like Valter Longo, he points to these people who lived to 105, 110 in the mountains and they’re 4’5″, they’ve never smoked a pack of cigarettes, they had sex once in their life for procreation, and they don’t drink, and they eat a thimble full of food every day. He’s like, “Well, that’s not how I want to live.” So yeah, this is the grail. How do we get all this, right?

Dr. Weitz:            Right.

Dr. Shade:           True to anybody out of academia, let’s do a one hit wonder and cut to the chase. It’s going to take a couple of things all in balance. So he tried to just run it on resveratrol in the beginning, and then they had some studies that were like, “Ah, I don’t think this is working.”  Here’s what happens. If you don’t have enough … Remember I said the sirtuin that get activated has a place for NAD, which is the primary space, it’s necessary, and then it has a secondary space for a sirtuin-activating compound. Well, it turns out if you just jam in tons of sirtuin-activating compounds, it almost sucks the NAD in like a magnet. What does it do? It takes it away from the mitochondria. So then the mitochondria start misfiring. So you have all these sirtuins activating and you have mitochondrial dysfunction.  You can’t drive it with one. If you want to drive the sirtuin-activating compounds, you need to supply enough substrate to have NAD balancing it. Then if you’re going to do that, you need enough methylation factors to balance that, but that’s not that complex of an equation, but if you try to just press one of the damn buttons, it doesn’t work so well.

Dr. Weitz:            Right. Yeah. I think to this day Sinclair takes a gram of resveratrol a day.

Dr. Shade:           Yeah. Yeah, he does, and he takes a gram of NMN, and he probably takes some maltenes. So he’s got it all held up there, but in the beginning, they tried to do it just with the resveratrol. Notice, that was where all his work started. The last couple of years, he’s been all NAD. So he must have been like, “Yeah. What am I missing here?” and then he got all into NAD.

Dr. Weitz:            Yeah. I remember there was a point at which he was the guy who was going to solve this longevity problem, and then there was a point at which it’s like, “Yeah. That’s it. That didn’t work. Forget it.”

Dr. Shade:           Yeah, but don’t throw the baby out with the bath water, just what did we have to balance with that. I had this great paper I found that was biochemical archeology. They were talking about the balance between NAD and methylation, and they were talking about these different societies that grew up and which ones thrived and how the balance of methylation and NAD gave them this power. They were describing if you’re low NAD to begin with, you’re not going to get anywhere, but if you’re high enough NAD to get somewhere, then later in life, if you’re imbalance one way or the other, you get Parkinson’s either way, but there are different Parkinson’s. So there’s the high NAD low methylation Parkinson’s and the high methylation low NAD Parkinson’s, and then there’s the balance. When you balance the two, you raise the whole human potential up. I mean, that’s beautiful.

Dr. Weitz:            That’s beautiful.

Dr. Shade:           The language, spreading fields of proteinopathies, which are uncoupling electron flow from proton flow and spreading fields of proteinopathies leading to the metabolic diseases and degenerative diseases of cancer and neurodegenerative problems. Yeah, exactly. Balance that thing, raise them both up, and just hit hard.

Dr. Weitz:            Let’s talk about senolytics and senescent cells, they’re called zombie cells because they don’t function the way they’re supposed to.

Dr. Shade:           Yeah. So the senescent cell, now, it’s a mitochondrial dysfunction or a toxic insult that causes telomere attrition, that then progresses to mitochondrial dysfunction, and then the mitochondria start releasing these pro-inflammatory mediators that diffuse out through the cell. The cell stops, it goes into growth cycle arrest, stops reproducing, and it just sits there, and it releases pro-inflammatory mediators, which are spreading decaying inflammatory fields throughout the body, but they’re also recruiting other cells into this decaying inflammatory field.  That’s one of the major causes of the propagation of all that inflammation that shrivels us up and makes us old and decrepit. So the idea is to get rid of these cells. So there’s two ways. You can reverse them and put them back into growth again and have them repair their mitochondria, and that’s if they haven’t gotten too deep in, and that’s by having good Nrf2 and AMPK activity that restores the milieu inside the cell, restores the redox potential down to highly reduced, and it can come back on and reboot.

The other is to kill it, and that senolytics, senescent cell. Lysis is cutter. So senolytics, quercetin was the archetypal senolytic. Fisetin or fisetin came on as a really good one as well, but even things like resveratrol and pterostilbene and curcumin have some of this senolytic activity.  Now, measuring this is really a bit of a challenge. This is because when you come in with this, well, first, you’re measuring some of the cytokines, the inflammatory molecules that are coming out of these cells, but if you go in and cut a bunch open and kill them, there’s a burst of senolytic cytokines that come into the system. So the senescent marker actually goes way up when you’re addressing the whole thing, and then how long does it to take to come down?  So in our three-month trial, it went up and we were using tons of senolytics. It was quercetin and everything that we gave them, but we got the good shift in the genes. We just have to come up with more markers around that, but some of the trials that have been used with really high end design senolytics have really been able to reverse phenotypic aging in a lot of animals and in humans. So that’s a really exciting thing.  There’s a really cool question in there. Why the hell would you ever do that? Why would your cell ever do that? Well, one thing is for cancer surveillance. “Oh, my God! I don’t want to grow like mad with cancer. I’m just going to shut down the cell.” All right? So P53s do that, but then they don’t know how to get it out of there.

So then there’s acute versus chronic. Acute senescence say, “Boom! Ow! I just hit the edge of that desk there. I just broke a bunch of tissue in there.” All right? So now, there’s a bunch of cells in there that are going to go into senescence, and they’re going to sing the song of senescence really loudly all in concert. So it’s not just whispers of senescence. It’s like … and the immune system is going to hear the signal. It’s going to come in. It’s going to eat them.  So you can grow new tissue there. So that’s a programmed senescence to rebuild damage tissue, but when they’re spread all over the place, it’s just whispers, and the sound of inflammation may be loud, but the immune system can’t pinpoint where it came from and so it’s not going to clean up the mess. So that’s just one of the side effects of aging. So now we know that we can go in and clean out some of those cells and stop that inflammaging signal.

Dr. Weitz:            I guess there’s another compound now called spermidine that’s getting some play.

Dr. Shade:           Yeah. Spermidine, isolated from sperm. Hence, the name spermidine. You’re like, “Well, they must have got it from sperm whales. No, they got it from sperm, semen, and there’s a lot of spermidine in semen, and it’s-

Dr. Weitz:            Apparently, they can get it from wheat germ and all these other vegetable products, too.

Dr. Shade:           Well, that’s where they first got it. I mean, they’re not like lining guys up and-

Dr. Weitz:            Right. That’s where the name came from. Yeah.

Dr. Shade:           That’s where the name came from. Dr. Ruth Westheimer, remember, the sexologist, she said, “Oh, there’s so much good for things for you in sperm,” little Austrian voice, but apparently, she had the goods on spermidine.

Dr. Weitz:            It’s not as good for marketing, though.

Dr. Shade:           No, no. Every time I’m about to put in a product I’m like, “God, I’m going to have to listen to all this shit about this,” and it costs some fortune, but spermidine is really good for working on autophagy and mitophagy and senolytic activity. So I’m sifting through all the exact uses of that, but that’s looking like that’s going to be a really promising one.

Dr. Weitz:            Now, what about dosage? You read these studies and they say you have to have 250 milligrams of resveratrol, and your products, because they’re liposomal, have a lower dosage of a lot of these products. How do we know that’s the right dosage?

Dr. Shade:           Yeah. Our quercetin has a 25-fold increase in absorption. “Oh, there’s 20 milligrams of quercetin.” I’m like, “Yeah, multiply that by 25. That’s a lot of question.” The beauty of it is it goes right into the blood, and the levels in the blood, even at the 20 milligram level, you’re going to beat out 500 milligrams because it all goes in at once. It gets the peak dose in there. You think of a senolytic, it’s almost like chemotherapeutic. You need to peak dose to activate that, Nrf2, AMPK. Peak doses activate that. So it’s a beautiful way to do it.  Now, exactly what the right dose is? Even though, “Oh, you need 250 milligrams. This study …” we’re still really working that out. I know that the dosage schedule that we laid out in our Bio-Age Reversal works because I was able to shift the whole genome plaque back. So I know that’s working, I know that I saw the markers of senolytic activity go up that I was breaking down these cells, but it’s going to be a few more years of really getting the right assays, working out, what we really want to see to know exactly what it is, but I have people go on these little campaigns, “We’re going to detox for a while and maybe we’re taking 40 milligrams a day, 50 milligrams a day, I’m stacking a couple of things together,” and there you’re actually getting maybe a few hundred milligrams a day in these nano forms.  I know that we’re triggering it. I know we shift fatty liver. I know we’re upregulating Nrf2. I know we’re shifting the genome. So I know that these dosages are working, but will we get to more specific dosages, more clarity to them? Yeah, we definitely will, but I also did do sirtuin upregulation tests on people using peripheral blood mononuclear cells. So the white blood cells are the only blood cells that are really cells. Red blood cells, they don’t have a nucleus, they don’t have mitochondria. They’re not cells. They’re just oxygen transport. So you do it in whites.

This is really nice. We saw on a single dose of it was basically our AMPK charge, but it was a little bit different. It’s a product we’re going to come out soon. Single dose, over about two, three hours, the sirtuins upregulated about three, fourfold and they lasted 24 hours. So it was really nice because I like people to do these things in spurts and then take a couple day off, go a couple days, take a few days off because you’re stimulating the system, let it come back down, stimulate it, let it come back down.  So the way that we’re using these and we’re dosing them, we see the signals, we see the changes. We know we’re working well on them, but I want to get to a point where I’m like, “This dose for that, that dose for that, that dose for that.”

Dr. Weitz:            I also have a request. Is there a way that you could put your products in a capsule form as well as an alternative to some of the liquids?

Dr. Shade:           Yeah, and we did start doing that. They’re called SED systems, self-emulsifying delivery systems. So our CDDPN is that way. Micromanager, which is more for controlling microbial growth, but we are doing one that’s a sirtuin activator in a capsule and there’s more that capsule activity to come. In fact, maybe as we work out some of the senescent stuff, maybe we’ll do a senolytic in there as well.

Dr. Weitz:            Yeah, that would be great because some people prefer the liquids. Other people, they don’t like to taste and you have to go to the fridge all the time. So they don’t travel as well and stuff.

Dr. Shade:           Yeah. Yeah. So we are doing that.

Dr. Weitz:            Cool. Excellent. So any final thoughts and-

Dr. Shade:           No, we did good. We covered a lot of stuff.

Dr. Weitz:            Yes, we did.

Dr. Shade:           The only other thing we didn’t really talk about is membrane health, and the membranes are … We’re talking about phosphatidylcholine bilayers that are housing the cell, ones that are making up the mitochondria, ones that are making up the endoplasmic reticulum. Everybody loves the mitochondria, but the endoplasmic reticulum is this big, huge folded over just layer and layer and layer and layer and layer of membrane that are creating what I call the membrane potential, which is a power potential across, it’s a charge potential across a membrane that actually drives the number of the reactions or the little motors like ATP synthase that are in the membranes.

Then the membranous organelles all communicate one to another, and the quarterback of that is the endoplasmic reticulum, and they actually exchange signals and discuss between the mitochondria, the golgi apparatus, the endoplasmic curriculum with signals coming from the extracellular environment through the cellular membrane, all that decision making going into the nucleus and signaling which genes to be manifest within the nucleus depending on the availability of inputs and the extracellular compartments and the health of the intracellular compartments.

So it’s a really beautiful communication structure and building membranes with phospholipids like phosphatidylcholine is one of the best ways to build the health of the membranes, and that was my one fun thing when I went on to a retreat with Joe Mercola, Ben Greenfield, Robert Slovak, Emily Givler, Bob Miller, and a couple other people. Joe brought his bioimpedance meter that was for measuring membrane health and he measured everybody there. Then I was the last one to get there, and Emily was like, “Chris is going to win.”  Joe’s like, “Why?”  She’s like, “Membranes. PC. He’s the PC guy.”  Of course, I beat everybody and I had these great numbers there because everything that I take has phosphatidylcholine, and you can buy it directly. You can buy our Pure PC or our Membrane Mend or various ways to get PC, but building the membrane is the one thing, and that was in Europe. That was the first mitochondrial therapy was lipid replacement therapy. There was those old injectables, Lipostabil and capsules of PC.  So the membrane is a big modulator of the power of the system. So we’ve been talking about cleaning up, burning cleanly, powering up the system, the NAD, the sirtuins, getting rid of the senescent cells, and just having a high powered system and the transducer of the power or the capacitor of the power being the membrane.

Dr. Weitz:            So the main ways to stimulate the membrane is with phosphatidylcholine, fish oil. What else?

Dr. Shade:           Yeah, those good fats there. Those are the core, but where else can you get PC? So you can get it from lecithin, but don’t get cheap soy lecithin, even cheap sunflower lecithin. Go for the professional grades. We have it down into a nano form in the Pure PC and the astaxanthin, and then these really good carotenoids for protecting the membranes, and that would be like astaxanthins, zeaxanthin, lycopene, tocotrienol. Those are super good, and then other natural source. When I first started into this and it was watching a lot of Dietrich Klinghardt, egg yolk, organic egg yolks. Six of those give you a massive PC dose.

Dr. Weitz:            Interesting. There’s some cardiovascular literature to say that choline can raise your TMAO levels and that can be problematic depending upon your microbiome.

Dr. Shade:           Yeah. It’s all backward. Your microbiome turns choline into TMAO, but the TMAO isn’t actually what’s causing the cardiovascular disease. What gives you the biggest spike of TMAO of any food in our biosphere? Do you know?

Dr. Weitz:            Salmon.

Dr. Shade:           Yeah, fish. Fish are all at the top, and those are the heart healthy ones. So the thing is the heavy meat eaters get a microbiome that makes TMAO, but they make a whole lot of other things. That firmicutes/bacteroidetes blend goes in the wrong direction when you’re not eating enough plant matter, and there’s all these other things that happen that move towards the inflammation of the cardiovascular disease. TMAO is just a side player in that. I don’t believe it’s driving it at all. In fact, after that paper came out, there was a bunch of Swedes, I think, wrote a big response to it called Something Fishy About TMAO.

Dr. Weitz:            Right. Yeah. It’s never made any sense to me, but it is out there supporting membranes, and then you also talk about the importance of the hypothalamic pituitary adrenal access.

Dr. Shade:           Yeah. That’s coordinating mitochondrial health. That’s coordinating all of your hormone health. Yeah, we can do hormone replacement, but adaptogens are probably the best way to just make sure that all of that is working really well, whether you’re taking exogenous hormones or not. One of the things that’s cool about ginseng is it raises the receptor density for androgens and estrogens. So as we get old, our androgens and estrogens are going down, but if our hormone density goes up or our hormone receptor density goes up, the activity, the androgenicity is a interaction between the hormone level and the receptor density.  So if you double your receptor density, you double the reactivity to a given level of hormones, and that’s one of the beauties of the adaptogens. In fact, the adaptogens, all the good ones, the astragalosides, the ginsenosides, withanolides, which are from ashwagandha, gypenosides from gynostemma, all of them have the same steroid backbone of your hormones. So they’re obviously meant to be interacting with your hormone system and affecting receptor sites, and that’s why they work so good on that.

Dr. Weitz:            Yeah. I wanted to mention the Astragalus situation because I know there’s that TA-65 supplement out there, which is this, I guess, specialized form of Astragalus, but can we get that from other forms of Astragalus?

Dr. Shade:           So there’s is cycloastragenol. Now, that’s what’s come out. There was a freedom of information act request to get the formula there, and it was cycloastragenol. Now, there may be some synergistic factor in there, but cycloastragenol is the core. So in our Longevity Elite, we have all these ginsenosides, and we have special astragalosides. We have cycloastragenol and astragaloside 4. Astragaloside 4 upregulates klotho, which is a regenerative molecule you make in kidneys and brain.  The cycloastragenol works for telomeres activation to lengthen telomeres, but one of the things … Dr. Raffaele has been working with TA-65 a lot, and he thinks that … See, cyclo is also a killer senolytic, and he thinks that a lot of the senolytic activity is responsible for the regenerative capacity of TA and the astragaloside. So now, they used to have the market cornered. Now, there’s other ways to find cycloastragenol and astragaloside 4, but whether it’s working at a telomere level, a senolytic level or both seems to be good. That seems to be good is freaking great.

Dr. Weitz:            It’s interesting how hormones started out to be one of the first places a lot of doctors and researchers went for longevity because they send signals to the body that things are good, that things are strong to build, to get stronger. We know people get older, they get weaker, they can’t function, and now it seems like all we’re hearing is that anything that tells the body that things are okay is not good for longevity and all these pathways that tell the body that we’re lacking, that we don’t have enough is where we need to go, but somehow, I think there’s got to be a balance.

Dr. Shade:           Yeah. It’s a balance of the two. There is no doubt at all that hormones are increasing your health span, if not, your total longevity. I mean, that’s just to say that they will wipe the slate clean. Most of these things that helping longevity are hermetic, and there are little stressors and you respond and clean it. You can overlay those on top of the hormone signals, and they’re not going to cancel each other out. Doing both is where you want to go.

Dr. Weitz:            Let’s consider that Fahy, which we mentioned, publishes the first study to improve biological aging, and he used DHEA and growth hormone in his-

Dr. Shade:           Oh, yeah. No, absolutely. Growth hormone is absolutely correlated with decay. There’s so many guys who do test in growth hormone and it’s like, “God! I feel freaking great,” and that is regenerative. So these other things are cleaning up. So you come in, you have a little Nrf2 activity, and you have some AMPK activity, some sirtuin. That’s taking out the trash, but the power is coming through the HP everything system.

Dr. Weitz:            Great. Another awesome discussion, Chris.

Dr. Shade:           Yeah. It’s been a great one.

Dr. Weitz:            Yeah. Yeah. I’ve really enjoyed this. I think we hit a lot of interesting science.

Dr. Shade:           Yep. All right.

Dr. Weitz:            Okay. Well, thank you, and I’ll talk to you soon.

Dr. Shade:           Thank you. Take care, Ben.



Dr. Weitz:            Thank you for making it all the way through this episode of the Rational Wellness podcast, and if you enjoyed this podcast, please go to Apple podcasts and give us a five-star ratings and review, that way more people will be able to find this Rational Wellness podcast when they’re searching for health podcasts.  I wanted to let everybody know that I do now have a few openings for new nutritional consultations for patients at my Santa Monica Weitz Sports Chiropractic and Nutrition Clinic. So if you’re interested, please call my office, 310-395-3111 and sign up for one of the few remaining slots for a comprehensive nutritional consultation with Dr. Ben Weitz. Thank you and see you next week.


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