[Music] Okay, welcome to Biohacking Beauty, the podcast that brings all the science of longevity and translates it to skin health. I'm Amit Ayeshel, this is. Anastasia Hujaywa. And we are the co-founders of. Yangos skincare. Yeah, which is the first world's first biohacking longevity skincare. And we are today, we have a very special episode. We're going to talk about one of the hardest subjects, the subject that we were pioneers of, I would say. But before that, we're going to read their review. Okay, okay. I found the perfect review for you. It's short and sweet. And Anastasia wants to conserve her voice. So I'm going to be reading their review. Every week, we're reading a review of one of your. The people who listen to this podcast and the reason is because reviews really allow us to basically be more discoverable. And that means we can help more people provide the information that we believe people need to hear in order to have better skin. So we give back. If you read your. If we read your review, you're going to get a free product from us. So you write it. You text us on Instagram or you write an email to
[email protected]. And we're sending you a free product. And the review today is by a person called Dark Queen Biohacker, truly aging in reverse. She's saying, I'll hit 60 in just a few months and consistently have ladies asked me what I do for my skin. I have never done fillers or had plastic surgery and have used young goose for at least three years religiously. I love how the company continues to invest in their product line and continues to bring transformation in a bottle. And I'm assuming the fact that she listens to this podcast help as well because you get information that you can apply. But then, Cecia, I want to start with a number today. Okay, hit me with the number. Okay, by middle age, by the time you're 45, 50, you've lost half of a molecule that basically runs your entire skin. Half gone. Crazy. And it gets worse than that. Believe it or not. Because the enzyme your skin uses for DNA repair, which is part one, consumes up to 90% what's left in a single UV exposure of that molecule. So you're studying with the half and one afternoon in the sun, just you know, had a walk in the sun. And it nearly wipes out the rest. The molecule, if you guess that or you read the title of this episode, the molecule is NAD+. And today we're tearing this thing apart what it does, why it disappears. And exactly what you can do about it, right? So ready. Let's get into the data. And I want to also say that it's one of the most requested podcast episodes. We did extensive research and we're going to have citations for all of the articles we put together to provide you guys the most up-to-date scientific information. Yeah, well, this we've been living and breathing no pun intended. We've been living and breathing the molecule, especially as it applies to the end for the last. Yeah, it's easy for us because we are new after date. But yeah, I'm excited to and we've recorded podcasts on NAD+. In the past, you can refer to them. They're still accurate. But what's exciting is that the field, as you mentioned in the beginning of this podcast, now the field invests so much into research on NAD+. So you get more and more and more discoveries. And that's why we also have been changing some of the things we're doing and how we are approaching working with the molecule. But now let's talk about why it matters for the skin. Okay. So, Anastasia NAD+. I always describe it as a rechargeable battery inside every cell. Because what really does like picks up energy from food delivers it to mitochondria. And without it, your cells just go dark. The analogy we give a lot is if we took it away from the body magically, you're going to die in like 30 seconds. But is this an oversimplification? Yes, it is. And I'll tell you why. The fact that the analogy of rechargeable battery, it's a good one. It's a good starting point. But it really undersells the scope of what that molecule does. So NAD+. participates in over 500 enzymatic reactions. It's not just an energy shuttle. It's one of the most versatile molecules in human biology. It handles both glycolysis and the mitochondrial electron transport chain and many, many other reactions. So the battery captures part of it. But it's more like an electrical grid because it functions as a substrate. So effectively is being consumed, which the battery part is not touches on it. That's not touch on it. So somewhere it's like a hybrid between like a like a battery and a jar of cookies. No. But you know, 500 reactions, that's crazy. Okay. So it isn't a supporting player. It's more of a like a major, the main role in skin aging and in aging is in general. But here's what I think most people miss. NAD, and when we say NAD, we just leave out the plus part. It's the same thing when we talk about so NAD doesn't just, you know, carry energy, right? As you said, it gets consumed. It gets used up or destroyed. And that's where the aging story starts, right? Exactly. There are three families of enzymes that consume NAD+. as a substrate. The first one, the one that most biohackers heard about, is third one through third seven. These are NAD+. dependent DS satellites, which is just a fancy way of saying that their job is removing the digital group. And every time they remove the digital group from a target protein such as B53 or NFK, Kappa B, they break down one NAD+. molecule. They're essential for DNA repair, information control, and cellular survival. So essentially we are paying with NAD+. For those processes, repair, information control, cellular survival. So what you're saying is that every repair job, every time your body comes in inflammation down or creates collagen, it's burning through NAD to do it. Exactly. Like paying a toll, basically, every time you cross a bridge. Yeah. And when you mention the battery analogy, that feels like, oh, it's just a battery. We can always feel, we can always recharge. But when you understand that it's getting used up, then you kind of can already start seeing the picture of how it declines over time. Yeah. So what about the second family? Yeah. So the second family, PARP, which stands for poly ADP ribos polymerases, PARP one is the one that matters most for skin. When UV light breaks down DNA, PARP one builds scoffalding to recruit repair proteins. A single significant UV exposure can deplete up to 90% of that cells NAD+. So that skin cell, NAD+. Remember, NAD+ is responsible for so many, many important processes. Boom. 90% I got because you've undergone significant UV exposure. Yeah. So one sunburn, basically. That's crazy. And sometimes I refer to certain twins, which you mentioned, certain ones, the third seven, like the police of your cells, of your DNA expression. PARP's are more like the fire brigade. Right? So imagine if you have a fire, who's going to get the precious gas? You're not going to give it to the police. You're going to give it to the fire department because they need to extinguish the fire. But on the other hand, during many fires, there are looting. So you're basically starving the police. You're basically starving that normal orderly kind of behavior from DNA expression. You can find the police and you don't want to do that. Yeah. Exactly. So then there's CD38, which you've talked extensively about before. We talk a lot about it, probably off camera most, but we talk a lot about it. And this is the, I would say, the villain of the story. And enzyme that just devours, I call it NAD Pac-Man. It just devours any D constantly and it gets significantly worse with age. We're going to come back to CD38 in the later on in this episode because it's the key to the whole gradual decline with age. Yeah. Right. And the other side of this equation is replenishment. So your cells recycle NAD applies through the salvage pathway, which handles about 85% of turnover. The rate limited enzyme is NAPNAMPT. Every time we mention it on the podcast, I always thought it converts left
over on your catenamide back to NMN, which then becomes NAD+. The speed of NAMPT determines the ceiling on your NAD+. And this is very crucial. Yeah, and here's the double hit NAMPT drops the amount of NAMPT that enzyme drops with age. So you're burning through more NAD, while recycling or making less of it. So your paycheck is shrinking, but your bills, they keep going up, right? Yeah. When you look at skin specifically, what are the effects or what are the downstream consequences of everything that we've discussed? Yeah, it's a multi-system crisis really. So fibroblast need NAD+ for certain one mediated collagen production. Keratina signs needed for parp 1 DNA repair, stem cells needed for ATP to divide. And critically, the timing of all of these processes depends on NAD+ oscillators tied to the circadian clock. So it's not one pathway. It's an interconnected network with NAD+ right at the center. And that's the part that I feel that I want people to really hear, right? This I want to make a sure, you know, the anti-social club. I want to make some sure that I don't have the right phrasing, but a shirt about like anti-single molecule companies, you know? Many companies saying, "Hey, this thing is going to solve all your problems. This is all you need in your products." And I'm against it. And this is why, you know, we're not like in specifically like an NAD skincare company, even though we were the first ones to introduce an AD into skincare. And within this, within our discussion right now, we are talking about a single molecule, but many different mechanisms. So I want that's the part I want people to hear. It's not some trendy supplement ingredient. NAD is the molecule. Every skin cell depends on, by the way, every cell, but every skin cell depends on for every function that keeps you functioning younger or looking younger. So when it drops, or looking young, by the way, in general. So when it drops, everything drops with it. Yeah. Okay. So do you want to quantify the decline? Yeah, let's quantify the decline. Because numbers here really are alarming. So at 2012, a plus one study by Misuri measured NAD plus across 45 human tissue samples from ages zero, so like newborn to 97. Skin NAD plus in adults over 50 was up to five fold lower than a neonatal tissue. That's approximately 10 to 25% lost per decade after your 20s. So five times lower, you know, because normally we say, oh, you lose 50% by that. No, you have 50% what you need. You have five times lower, right? By the time you're in your mid 40s. I remember the first time you showed me that paper. I thought it was like a typo. So if your skin cells were like a bank or a bank account, you went from 100 grand to 20 grand in saving like immediately. And the bills, they don't change. So if anything, they go up. They go up exactly. So now talk about CD 38. Because this is where the story gets really stressful. Yeah. So CD 38 was identified in 2016 cell metabolism paper as the dominant NAD plus consuming enzyme in aging tissue. So it's an acto enzyme on immune cell surfaces that hydrolyze this post NAD plus and NMN. It's expression increases two to three fold with age. So you actually make, remember, you have less and less NAD plus. And as some kind of like bad joke, you actually make more of CD 38 that consumes NAD plus with age. Yeah. So the mechanism behind that increases what's really fascinating. This is the part that really blows my mind or blew my mind. You told me, remember, as having a conversation, you told me CD 38 doesn't just like randomly go up. It has a close relationship with zombie cells or sent us in cells, right? Yeah. They're to people who are newer to the podcast. These are damaged cells or older cells that instead of going through a the normal process of elimination by the body, they stick around. And they don't the reason they're called zombie cells is they don't just stick around. They also pump out inflammatory signals. And these activate macrophages, right? Which are those immune cells that we talked about, which crank out CD 38. Exactly. So at a 2020 nature metabolism study, mapped the entire feed forward loop. So senescence triggers SASP. SASP activates macrophages, macrophages express CD 38, CD 38 destroys NAD plus and low NAD plus accelerates further senescence. When they clear out senescence cells in mice, so they they made genetically engineered mice that didn't have senescence cells in them. They preserved 60% more tissue of NAD plus over six months. But before everyone jumps to conclusions, I do want to point out that unfortunately a lot of studies that look great in mice don't pen out in humans. So this looks promising and it has a merit to it, but let's not assume it's one to one in humans. Got it. But there is a you know a tight relationship between like more senescence cells and more CD third or more senescence cells, more CD 38, lowers NAD, lower NAD causes more senescence and the cycle goes on, right? Yes. So as we say, it's a vicious cycle that feeds itself. But I'm not so sure. Let's make this maybe more digestible. Yeah, more tangible. What is the person that's watching this or listening to this right now? Seen the mirror where when all of this is happening or when they're going through this. Yeah. So the first visible consequences is collagen loss. When NAD plus is insufficient, third one can't deacetylate B53 or suppress NF-Hapa B. So collagen production genes slow down while MMPs, the enzymes that degrade collagen get activated. So again, we're we're back into that cascade. It's like a very unfavorable unfortunately for skin. So at a 2014 study confirmed that restoring third one activity reverse these senescence markers in dermal fibroblasts. 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You can grab the link in the show notes below. So you're losing collagen faster while making less of its simultaneous. That's not just a gradual fade. A lot of the times we try to think of aging as this gradual process, but especially when we're talking about this regulation or MMPs, it's more like a collapse. Collapse happening beneath the surface before wrinkles even happen. So what else? Let's talk about mitochondrial function. So third three needs NAD+ to deacetylate the antioxidant enzymes without it oxidative stress builds in the mitochondrium and ATP output blamets. Which means less energy for everything. So cell division, repair, barrier maintenance. That's why older people's cellular turnover stretches from 21 or 28 days to 50 or even 70 days. Older skin, heal slower, it looks duller, it feels thinner,
And we even know that people that have undergone a lot of like rejuvenation procedures to their skin When they grow older if they haven't had maintained had not maintained longevity and we're talking about today This even is even exacerbated so they did a lot of things to like maintain you for looking skin and Then they get slower turnover and everything we've were saying now Because they've they've they've caused more fires, you know that parps need to turn off etc That's even the reason that the barrier itself breaks down right we hear a lot these days about skin barrier and compromise skin barrier That's a major player in skin barrier breakdown, right? Uh-huh. Yes. Um we're talking about the CD-30 being the major player. Well, I'm talking about like my like the decline of energy in general So like for example, you know anything that your cells need to do in order to maintain like skin barrier whether it is Seramide synthesis, you know, which would depend on any the enzymatic reactions, which would depend on any the Sort those sort, you know, yeah No, definitely the platythane deplase weekends just straight on corneum lipid bilayer Increasing transceptermal water loss and sensitizing skin to irritants and melana side regulation breaks down as well So, you know, you can a lot longer control the tyrosity tyrosity tyrosinase properly Late into uneven pigmentation. Yeah, I mean I'm telling you this type tyrosinase you've got to con you got to What did that a control anyway? So yeah wrinkles, dullness, dryness, sensitivity, dark spots all of it kind of traces back to the same root cause which Was this one molecule declining? I think and and we hear a lot about you know, we've heard a lot in the last I know how many years in skin care Oh for pigmentation you need to do this and that for wrinkles you need to do so to do this and that well at the bottom line if you are not Repleting your might replenishing your mitochondria Or replenishing nad you are your only covering covering up symptoms and I think that's why there is a There is a real cult around nad now because we it's so important. Yeah So let's do supplementation deep dive next We'll talk about an amendment and are a nice thing So the encouraging part of this story is that nadiplastic line is reversible There are three well-studied oral precursors and they're not interchangeable So I mean, I know you have strong opinions here. Do you want to voice your opinions? I do but let's give people you know data first because that's why I have opinions there so Well, that people decide and I'm gonna Gonna stay quiet, but walk us through an amendment for example, okay An amendment so an amendment is nicotine amide mononucleotide and it seats one and the magic step from nad+. In 2018 researchers found a dedicated Transporter in the small intestine that specifically absorbs an amendment That direct route is unique among the precursors and that matters because it means an amendment doesn't need extra conversion steps to enter Your cells, right studies again like we're talking about studies that we've been looking at for the last decade or two What we see a lot is that it reaches muscle heart Brain blood vessels tissues like your skin depends on depend on it for nad supply Through circulation right through being Basically having high levels of it throughout your body, right? Okay, so if we go back to the studies in 2022 multi-center double blind placebo controlled trial in neuroscience tested 300 600 and 900 milligrams daily so those dependent nad+. No serious adverse events, but I want to plug a caveat in 2024 science Advanced paper found most oral and the man actually gets converted to nicotine acid by god bacteria Before absorption The pathway to nad+. is more indirect than we initially assumed Yeah, to be honest this paper surprised me But I think the bottom line is that you it's still it's still the same you still get still nad goes up in the tissue Yeah, some people you know thought or maybe like god kind of like god bacteria takes it for themselves yeah, and that Kind of lowers amount of nad+. You derive from supplementation, but I think it just basically shows that You know there is a it's more complex. It's not as direct like we mentioned by the goodness Yeah, it goes up and this is the precursor like spoiler a lot This is a precursor that you and I take that we take about the gramma day With our first meal of the day in the morning and they're we're gonna get to why in the morning But now what about nr because I know You've looked into the data very closely there. We were definitely very interested in nr In the early days. So what about nr? Yeah, yeah, we even had A time of nr basically ingredient centered and r has the most clinical evidence Over 30 human trials It requires two enzymatic steps which are n r k1 and n r k2 through processes. It becomes an amen Then and the man becomes nad+. Across overestatied showed 1000 milligrams daily raised blood nad+. By approximately 90% in two weeks That's Crazy so 90% remember we do it you know one UV Yeah, you know one UV Major UV exposures lowered by 90% this is like 90% over two weeks, which is incredible So that obviously that's very dramatic. So Why would someone choose nm n over nr or vice versa? So it's really really great question. So it's all about tissue distribution Animal data suggests nm n elevates nad+. across a wider range of tissues Which are basically muscle brain kidney vascular and r concentrates more in the liver and blood For skin which receives precursors through dermal blood supply systemic levels matter But an immense broader reach maybe an advantage got it. So and then there's Niesin right so five dollars at your local CVS So what's the deal breaker there like why are we talking about these two precursors and not nice? Yeah, I mean nice and Try to make itself viral for nad+ supplementation and I mean definitely biohuggers on the budget I think most of them tried it because there is a pathway, right? But the deal breaker would be flushing So about about 50 milligrams nice and triggers What's called gpr 109 a receptor activation and prostaglandin d2 release So it's intense skin redness worms E-chain I've seen you go through that, you know and yeah, and it looks scary He just turned all red was hat was each and everywhere and then take it allergies from time to time So he's used to itching But that was like crazy. I mean most people find it intolerable It also raises liver enzymes at sustained high doses So that you know, you would have to like then go in the d8 that It's not practical for targeted any deplus, you know So it's more like yeah, I do take it when I go into the sun and there's a different story So no, no, I know you don't take it for the nad+ raising, you know as a supplement But I just I've seen you go through the And this flash and I know other people have and So the story is this I just want to say the story is that I drink a shake and took nason And I guess my god wasn't like, you know, into digestion basically So it didn't digest and then I went to the sauna and after that I had a meal And that kicked That broke down the nason like my god broke that broke so it was outside of the sauna already So that's why it was unexpected But anyway, here's my hot take NN men hot take honesty, okay like NN men is My first choice For you know broad spectrum nad supports We both take as I said one ground daily or a thousand milligrams the same thing with our first meal NR is if you want the deepest safety data set or The reason I'm the reason I want I want to emphasize that NR Is a patented form so there is more incentive by a specific company To research it that is why when I say oh there are many studies You know it's there is the most data about safety It's because other studies could be biased for that matter It you know the fact that there are 30 studies there is a higher incentive in researching it However, we know it's safe So niasin I would say is only for basic B3 sufficiency and you should So basically take the daily recommended dose of it and that should be enough There is one thing I want to add, which is the reason we were
recommend taking NAD precursors in the morning is because NAMPT peaks with your circadian rhythm. So it peaks in the morning, you have more ability to kind of recycle, and etc. in the morning. One thing I'd add is that high dose precursors increase nicotine and mitephlax, which can strain your methylation pathways. So to alleviate that, consider stacking TMG tri-metall glycine at 500 milligrams as a metal donor. So basically, we say it to the one ratio, which means that's what you said about 500 milligrams. So in the case that you take 1000 milligrams of it precursor, that would mean that you should take TMG or another methyl donor at about 500 milligrams. Right? And by the way, great product to take in general, tri-metall glycine, a lot of studies behind it. But yeah, so this episode was kind of the first part of our deep dive, nerding out about a molecule that we love, and we feel that since it's becoming extremely popular, even in skincare right now, there are nuances that we want to cover. So that was more of an intro. We talked about what it is, what it does, what it does in your cells, etc, which was great. In our next episode, we're going to talk more about the applications of it in skincare, which is a whole different challenge as far as absorption, formulation, stability, delivery, a lot to unpack there. Different, we talked about TMG as something that you want to take with it in skincare, completely different set of ingredients you want to have. Exactly. So stay tuned for part two. Yeah, and thank you everyone for listening. We hope it was enjoyable and we'll see you here next time. Bye. Bye. (upbeat music)
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