The Secret Molecule for Endless Energy | Dr. Andrew Salzman : 1253

What is nad?

NAD is a small molecule. It's the centerpiece of biology, and it really does three things in our body. Gives us our energy, protects us against oxidants, and it saves us from cancer. We used to think about diseases as being sort of these isolated instances of bad luck. Oh, I got diabetes. Oh, my goodness, I got cancer. But that's the 1950 ways to look. Today we have to see these really as an integrated whole. Why do we get sicker as we get older? The aging process is a core fundamental derangement that then spawns injury in all these different organs. If you happen to have an injury in your knee, suddenly you have arthritis. But if it's really not arthritis, what it is fundamentally is aging.

I look at it like this. If I age, it's my fault.

A lot of people think that aging starts when you're 60 and 70, but actually aging doesn't start when you're 65.

Given what we know with AI, with new research, all the work you've done in your life, how long do you think humans could live if we just pull out all the stops? You're listening to the Human Upgrade with Dave Asprey. This is going to be a really fun episode recorded live in the studios here in Austin, Texas, because I like talking with really, really smart people who've done a lot of big things in the world. There's so much we can learn. The episode today is about longevity. It's about NAD, and it's with a guy who's only written like 170 scientific publications, 50 patents, and the guy who created the first PARP1 inhibitor, which is really, really useful in preventing cancer. He's also the chief medical officer for Wonderfeel, which is a new NAD focused company making some supplements that are, I would say, the next generation of what's happening in the world of nad. If you're new to the show and you don't know what NAD is, we're going to go into that. This is a compound I wrote about my longevity book, and it's a compound that you've heard from maybe David Sinclair on the show talking about it. And it's something that's very fascinating because if you can control your NAD levels, you can control one of the many pathways of aging that you need to control if you want to live to at least 180 like me. So let's bring one of the luminaries in the field onto the show to go deep on it. None other than Dr. Andy Salzman. Andy, welcome to the show.

Thank you very much.

You're an interesting guy. So you were a practicing physician, Harvard kind of guy, and then you suddenly one day decided, I'm going to wake up and go do research and make drugs instead of being a doctor. Why?

I love taking care of patients and being at the bedside and helping people, helping children, talking to the families. I went into intensive care because I deeply cared about critically ill kids. But, you know, after, after about 10 years at the bedside, I realized that I wasn't able to do enough. I could work all night, I could take care of kids. But ultimately the real advance is when you develop a new drug or a new intervention that can save not one kid at the bedside, but thousands. Thousands that you haven't even met. And so I committed myself to research to do that.

Does it have to be drugs? I mean, could it just be.

No, no. Any kind of intervention, but something different. Something outside of the normal pattern of medical behavior that we are accustomed to in the hospital.

So something that scales better than, let's send everyone to the hospital, let's give them something that can work even if they don't have to go to the hospital.

That's right.

You're working with a supplement company, but you did a $600 million deal on a cancer drug you invented, that you sold to Genentech. So why the cutover from pharmaceuticals to nutritionals?

Well, I work in both areas.

Okay.

Okay, so I don't have a preference. Well, I will say I do have a preference, actually. I think that the non pharmaceutical approach today has become faster, it's richer in terms of the possibilities. You can exploit the pharmaceutical world for all of the good it can do. It's just very tedious and slow. And I want to get a lot done. I'm ambitious. I have a lot of things I have to do.

We're going to go deep on NAD in a minute.

Sure.

You have some interesting perspectives on this. If you wanted to create a new pharmaceutical, and I know you invent them on napkins in your sleep, probably. So you have this idea, how much money would it take on average to get a pharmaceutical to market in the.

U.S. oh, at a minimum, you're talking 75 to $100 million.

10 years. If you came up with a new nutraceutical, how much money would it take to get that to market?

250,000 to $500,000 in six months.

Okay. Why such a difference?

Regulation. Look, the concept of the FDA was good at the beginning. In the 1930s, they cared about people. They didn't want Anyone to get hurt. They wanted a certain type of procedure and protocol to follow. Every kind of new development for the sake of the good, do no harm. But it metastasized. It became so extraordinarily complex and involved that it just takes a lot of different things to do and adds up, costing money and time. No way around that.

Did you just say the FDA metastasized? I'm afraid so. I've never heard that before, and I can't disagree. And I've been involved in longevity medicine for 25 years on the nonprofit side, and just with what I do. And I've seen so many companies just leave the United States in order to get things done. And it doesn't feel like it's serving Americans or even the world when we have this kind of resistance. And I can see why you'd say, well, if I can solve a problem with a half a million dollar investment or $100 million investment, it's almost like they're punishing pharmaceuticals.

At some point, perfection becomes the enemy of the good. And it's a brilliant thing to have an absolutely bulletproof drug that's been through all of these myriad tests. Love to have it, but it takes too long. And if we rely entirely upon that process for the discovery of the next generation of drugs, we're going to be waiting a long time. I don't have the time.

There you go.

And a lot of other people don't have the time. The people who need help, who want interventions, who want improvements, they're not going to wait 10 or 20 years. We need to do it now. We have the knowledge. Let's apply it.

One of the things that drives me nuts in the world of longevity is you'll see some of these people saying, well, we have no evidence that you can extend human life, therefore you can't. And there never will be evidence because they would have to die. Meanwhile, we do have aging clocks, and we have the ability to measure all sorts of aspects of aging. So we can say, well, let's do what's most likely to be beneficial and let's see what happens. And I'm on that path. What do you think about the ability to measure someone's age and to predict whether we can extend their lives?

Well, aging is really two things. Aging is measured in years, which can be, as you said, a very long process. And we have to wait for people to succumb in order to know whether we've made a difference in mortality. But aging is also reflected in the quality of our health and our organ function, and we can use that as a proxy for longevity.

That's where I am. And I'm saying, if I can make my organs younger, I can make my mitochondria work better. And we can measure all these things. At a minimum, I'm going to have a really good time when I'm 80. And if I die on 86 on average or something, I still win. And the odds are very high that it'll be longer than that. I know our current best is 120 or so years. Given what we know with AI, with new research, all the work you've done in your life, how long do you think humans could live if we just pull out all the stops?

We have to ask ourselves whether the ultimate longevity of the species is determined in some type of inexorable and unchangeable way, or whether it's the accumulation of damage over time that ultimately forces us to succumb. If we look at more broadly at the ecology, we see animals that live two weeks and we see animals that live 400 years, like the lake shark. What we're learning by these experiments of nature is to better understand what are the underlying principles that guide their ultimate demise. And we know, for example, in the lake shark, which is such an interesting animal, 400 years old, this animal has massive duplications of DNA repair enzymes. So they have a tremendous investment on making sure they don't accumulate mutations. It takes so much energy to do that that the darn creature can hardly move. He doesn't have much energy left for anything else, but he sure lives a long. So there's a trade off from an evolutionary perspective where every species has evolved either to have a wonderful quick life with tons of energy, like the mosquito or the housefly, or a very long and somewhat slow life like the tortoise, or a giant tree that doesn't do very much, or in the case of the lake shark. So if we understand what are the fundamental determinants of a long life, then we can start to make interventions to specifically interdict these. And what we've learned from these experiments is that the lake shark and other animals like that have invested massively in protection of their genes, because ultimately it is the accumulation of mistakes of mutations that will ultimately lead to dysfunction, aging in the broad sense, and death.

The logo for my company, Upgrade Labs, the AI Exercise longevity company, is the axolotl, which is an animal that can regenerate limbs or even its entire spinal cord over and over and over. I'm like, okay, it can be done. How Do I install that in myself?

There's the possible one. Look, everything's based on knowledge. Knowledge is power. As we start to understand really what are the fundamental drivers of longevity and of death, that will give us the information from a scientific perspective to go out and make the right intervention. So I don't think 120 years is the ultimate barrier. It is right now because we really haven't made those changes we need to. But science is moving very quickly. So I would predict that in five to 10 years, we're going to start to see changes. It's going to be 130, 140. You know, at some point, maybe we'll be like the lake shark. I don't think so that far. Who would want to live 400 years? But I think we will make, we will crack that barrier.

I certainly think we can, and I'm totally willing to be wrong and just have a great life in the meantime. I've seen in my 20s, when my health was failing, I remember my, my friend Mike, who's on the board of the anti aging nonprofit. He would call me at 11:30 at night and he had more energy than I did. And just, I watched people reverse their age when they were in pretty advanced. I'm like, I wish I had that much energy. And so I've, I've seen it. They're outliers. But if one person can do it, then we gotta study them and figure out what caused that. And your relentless curiosity in your career, I think is pretty interesting because you've done a lot of different areas of work and you arrived at NAD as something to.

Oh, I've been focused on nad since 1985. Oh, wow, okay.

So you were early, early adopter.

Oh, yes. By 1994, my career was focused on, was focused on NAD. When I became involved in the PARP work, I recognize that NAD was the centerpiece of biology as far as I was concerned in the icu, because NAD powers parp. Oh, well, NAD has many important functions, but for parp, it is absolutely the critical cofactor parp. Without nad, it doesn't work.

Okay, let's explain what NAD is and what PARP is. So first, what is NAD and why do we care?

Well, NAD is a small molecule that, like I said, it's the centerpiece of biology. And it really does three things in our body. First of all, NAD is absolutely, absolutely essential for energy. NAD controls the production of ATP, which is the currency we use in order to think, to move our muscles, to have our digestion work, to Metabolize. So NAD is absolutely essential for the energy in your body. You have low nad, you have low energy. Okay, so that's the first thing. Second thing. NAD is absolutely essential for the production of an antioxidant defense. We are bombarded continuously by the environment, by cosmic rays, by oxidants. We make. We are in a bath in a world of oxidants. We must have an efficient and effective antioxidant defense. NAD produces or is converted to nadph, and NADPH is the driver that protects us. It produces glutathione, it produces all of the antioxidant functionalities. So we need NAD to survive in an oxygen rich environment. That's the second thing. Third, NAD is used by parp. PARP is the second most abundant protein in our nucleus. It enshrouds all of our. All our genetic material. Every minute. We are undergoing changes in the DNA because of the environment, because of oxidants and cosmic rays. And there are breaks, there are little. You know, DNA is a double strand. It's a helix, though. That helix is susceptible to nicks or breaks in one of the strands, and they're happening about 70 times a minute. So over the day, every day, we are having an assault on our genetic material. If we do not immediately recognize that and correct it on the spot, those breaks persist. And when the cells divide, if there is a break, you will have a mutation. Well, when you're 10 years old, maybe you won't have many. By the time you're 30, you're going to have a bunch. By the time you're 50 or 60, if it's not corrected, you will have loads and loads of mutations. And that spells malignancy. If you remove any of the DNA repair enzymes, you are going to get cancer. And the best example, of course, are BRCA deficiencies. Mm. So PARP is the enzyme in the nucleus that identifies the problem, the nicked DNA. It gloms onto it, it then twists and becomes active, and then NAD flows into it, and it uses the NAD to repair. So low DNA. No DNA repair mutations, ultimately malignancy. So those are the three things that NAD does. It gives us our energy, it protects us against oxidants, and it saves us from cancer.

And the protection from oxidants is gonna provide cardiovascular protection, right?

Oh, my goodness, yes. If you look at the vascular system, the oxidants that bathe our blood vessels, over time, those lead to endothelial dysfunction, leads to hypertension, calcification, all of the problems we have with plaque buildup. So, yes, it is A critical part of the vascular system, and then, of course, of the cardiovascular of the heart. The oxidant injury to the heart impairs the muscle function. So as we get older, we have a heart that beats less strongly and blood vessels that are more rigid. They don't provide the kind of blood flow and nutrition we need to sustain us. So the role of NAD in cardiovascular health cannot be underestimated.

It's funny, in the world of longevity I talk about, there's these four killers. If you want to live a long time, don't die first. So that would be don't get cancer, which we're talking about with NAD and parp, and then don't get cardiovascular disease, which is actually more deadly than cancer. And then what's behind both of those is don't get diabetes and then don't get Alzheimer's. And I look at diabetes as kind of the first of the four, because if you get that, your risk of the other three big things that'll kill you goes up.

We were the first to show that in diabetes. We published in Nature that in diabetes, you get a fall in nad.

There you go.

Right. And that leads to all the complications of diabetes on the blood vessels, on insulin sensitivity. This is all bound up with having a healthy level of nad. It's got. You've got to maintain NAD to maintain your health.

Longtime listeners have heard me talk about niacinamide, which is the very oldest way of raising NAD. And then the first research came out about NR about 18 years ago or something. I started taking it then. And then NMN came out. And so I've been on these things for a long time. I've done the IVs and talked about what that looked like, what is the benefit of taking nad, and what is the. Or NAD precursors, and what is the downside of taking nad?

In order to boost nad, there are only two things you have to keep in mind. One is you have to have enough there. You got to have a supply. And secondly, you need to prevent its consumption or its depletion. So let's look at each one of those. You were taking supplements and are initially then nmn. Why did you do that? Because NAD itself cannot be swallowed and expect to cross the gut into the blood and get into our cells. Nad. I mentioned how important it is, but it's important inside the cells. That's where it works. So if it's outside the cells, it's not going to do anything, even with an intravenous infusion. It's outside, even with an intravenous infusion. It'll be in your blood, but that doesn't mean it's in your cells. And when it works, it's got to be inside the cell. That's where it does those three things I mentioned. So how do we get it into the body? How do we get it through the gut? How do we get it from the blood into the cells? We use nature's own way to do it. Nature has designed a thought about this. So in our bodies, we have precursors, NMN and nr. And they're there for a reason, because there are specific shuttles that exist in the cell membrane that move these from the outside to the inside. Remember, NAD is a very precious molecule. God made it with charges on it. It's a polar charged molecule. It will not leave the cell and it will not get into the cell. It can't cross a fatty lipid membrane because it's charged. So in order to get stuff into the cell, there was a jacket created around it, if you will. That's what NR and NMN are. They're a jacket on nad. And that jacket is recognized by a shuttle, which whisks it into the cell and. And there the jacket comes off and NAD is alive and well and ready to go inside the cell. So the supplement industry recognizes this, and that's why NR and NMN dominate that industry. You have to supply those in some manner to get enough nad. That's the first goal. The second goal is you gotta keep it there, right? Doesn't do you any good to boost the stuff and get it all in there and then only find out that there are depleting mechanisms that scarf it away, that steal it away.

I think this is a problem that I ran into. But actually, first I have to ask. There's pretty good evidence that alcoholics who get 10 to 20 NAD infusions have a much lower risk of starting to drink again. And if it can't enter the cells at all intravenously, why are we seeing clinical results?

Because NAD in the blood can be converted by enzymes in the blood and in the tissues to NMN in nr.

So when I get an NAD iv, my body's converting it back to nmn.

Yes.

I did not know that.

Okay, yes, yes.

So you can save a lot of money by just taking the right supplements without having to do the IVs.

Not many people want to walk around with an IV.

Plus, it's pretty uncomfortable. NAD IVs. I finally got to where I could do a gram in about 45 minutes. But it's like something sitting on your chest and you're turning red. It's a methylation thing. So we can just stop doing that.

Yes. I would recommend good oral supplements that make sense, that provide the precursors, these jacketed forms of nad.

How much time I've spent with needles in my arm that I didn't need to. With the knowledge that we now have that we didn't used to. Yes, okay, that's fascinating. So let's say that I've taken some NR or some nmn. What's going to steal it?

Well, there is a. There are a lot of interesting theories on this, but now we know a lot more than we did five years ago. It turns out that there is a major enzyme in our body which has the specific role of clipping NAD or NMN and cutting it in half and destroying it. And that is called CD38. May have heard of this. CD38 is an enzyme that's present in most of our tissues. When we're young, we have just enough that we need, but as we age there's more and more and more. So by the time we're 50 or 60 or 70, we've got way too much of this. This enzyme is positioned in different places in the cell. There are actually three different places, but the one we about is on the cell membrane itself. It sticks out into the blood and as NMN whisks by it says haha, there you are, I got you. And it cuts it in half.

Why would this exist in our cells?

Because it needs to do that in order to fight infection. It is something involved in the inflammatory response. So a little bit of this great thing. There are three enzymes that use NAD or nmn. One of them is parp, I already mentioned, to affect DNA repair. The second one is the sirtuins, which changes a lot of the physiolog. And the third one is CD38 which uses it to fight infection. A little bit of something is a good thing. It's natural, we need it. Unfortunately, as we get older we get more and more inflammation, probably from leaky gut. And CD38 responds to that by being more and more expressed. And as we get way too much of it, by the time we're 50 and 60, it is out there and it is destroying the NAD. So you can take all the supplements you want, you can load yourself up with NMN, NR, but this enzyme's out there when you're 50 and 60 and it's chewing it up. So the right approach is give the supplements. Yes, great. Idea, but concomitantly with that at the same time, slow down CD38.

Okay?

And this is the key combination approach, which we think is the next generation approach.

So if you were taking extra NMN and Extra NR, your CD38 activity is going to go up and up.

CD38 is going up because of your age.

Does it go up even more when you have NMN and nr? No, I thought it consumed it.

It does, but it's an enzyme. It's not used up. When it catalyzes the degradation of nad, it is, it is an enzyme. It's being regenerated. You don't lose it.

Okay?

Yeah, it's just there and it's doing its thing, which is eating up your nad.

So if you wanted to live a very long time, you probably should brush teeth really well. Because if you have a lot of oral bacteria, which drives your whole microbiome and also escapes directly into the bloodstream, you're pissing off your immune system. You're living in a house with toxic mold, like I did as a kid, which causes strobe throat to grow as well. You're pissing off your immune system. So the more chronic infections you have, even low grade, the more you're going to have an aggressive immune response and the more likely. I'm just, I'm kind of making this up as I go along, but.

Well, all of the things you've said are absolutely true, but there's an even bigger gorilla in the room here.

What is it?

The real cause of the major cause of progressive inflammation as you age is the ability of your intestine to seal itself and not permit the egress of endotoxin, other bacterial constituents from inside the gut to the blood. We know that the major protein in the gut, which is the seal, the gasket, is Z01 and Z01. Unfortunately, as we get older, its levels go down. The gut gets leakier and leakier. Look, if you take a 25 year old person, they have trillions of bacteria inside them. None of them get into their blood. You take a 60 year old, there's lots of garbage coming in. And that garbage stimulates our immune system. And it says, whoa, time for inflammation. We have infection. And that infection, if you took a 70 year old person, they're inflamed. Aging is an inflammatory event and that inflammation turns on the expression of CD38. That's where it's coming from. So the microbiome and our ability to protect our gut is key. Proper diet. There are various things we can do about the microbiome. I'm sure you've talked about that in other shows. This is central to maintaining longevity because that starts the whole process. Our gut is the driver, ultimately the initiator.

In my longevity book, I referenced a couple papers that showed taking activated charcoal, which just binds to endotoxins in the gut, is associated with about a 15% lifespan increase, just from reducing some of those. And when you look at things like germ free mice where they have no microbiome because they live in little bubbles, they live a long time, they're ripped, they can eat whatever they want.

This is where I began my career really, in 1988. I was in the intensive care unit and there was a brilliant young professor that I teamed up with named Mitchell Fink. And we had the idea at that time that the barrier of the gut might change during disease. No one had thought about that. And I discovered that endotoxin can actually open up the gut. And we published these papers from'88 to'92 showing that it was malleable, that the gut was sealed, the barrier is not fixed, it can respond. And we found a lot of. We found that hypoxia will do that. We found that acidosis would do that. Certain cytokines and all of that work show that it's dynamic, that they're opening.

And closing the junction. How would you go about sealing as best as possible the gut so that nothing leaks out of it over the course of decades?

That's going to require, I think, understanding of diet and the role of the microbiome.

Okay, right.

That's not an area that I'm in anymore. But there's tremendously good research looking at that, and that's very important. That is a major factor in longevity. That should be emphasized. There needs to be more research in that area.

Okay. I've been for almost the last eight years now advising Viome, which has a really good data set now where they're starting to figure that out. I know that because I was on antibiotics for 15 years every month, because I had chronic sinusitis and strep throat, because I lived in a house with toxic mold, that I probably don't have an advantage there. In fact, the fact I'm not obese right now is kind of shocking given all the crap that I went through. And so I feel like I'm coming from behind in my longevity journey here. For an average person, maybe they're a little obese, but they haven't had that big of a problem. Is there a Pharmaceutical intervention or is taking these NAD things like you're making with Wonderfeel, where do you start?

Well, it's actually interesting now you're talking about a positive feedback loop. It turns out that, and this is also work that I did in 1992, the energy of the cell in the gut is directly responsible for how well the gut seals itself. We published the first paper on this where we related NAD and ATP levels inside the gut cells to their ability to maintain the integrity and not let MOLEC slip through. So you can imagine if that gets out of hand, out of whack, and then you start to leak and you get inflammation. CD38 expression goes up, NAD goes down. The gut now doesn't have enough NAD to maintain itself and it gets progressively leaker. It's a snowball effect. So the key thing is keep the NAD at a healthy level, have a good, healthy gut, do whatever interventions science is telling us to do, keep our gut good and healthy. And then to further augment that, take NAD supplements or actually NAN or nr and find a way, which I'll talk about a little later, to stop the activity of CD38, depleting this precious NAD that we have.

So even if you have immune activation as you age, you can stop the CD38 so that you can slow it down. Stop it, yeah, absolutely.

There are two approaches. There's the pharmaceutical approach. I wish them well. It'll be another 10 or 15 years. I'll be a little bit old at that time to enjoy the benefits. But I do wish them well because CD38 is a target that the pharmaceutical industry should go after while I'm waiting. We have botanical approaches, natural approaches, which we include actually in our wonderfill product, which slow down the activity of CD38. So that combination I mentioned is so critical. Give a boost with a supplement, but stop the depletion.

You mentioned ATP and I think a lot of listeners know what ATP is. Just in case we have some new listeners. Talk about ATP for a minute and what it does in the gut.

ATP is the ultimate means. It is a currency. Think of it as a cryptocurrency. It's a currency in every cell that is there. And it is the final common molecule that provides energy to various processes, whether they're metabolic processes, hormonal processes, movement of muscle, activity of neurons, and our brain thinking ultimately ATP provides the electron reducing equivalent, is providing the power to do things to make the body work. NAD creates the ATP. So if you don't have nad, you don't get ATP and why did I care about this? As an intensive care specialist, we're not worried about longevity in the long term in the icu, we're worried about whether you live the next hour or two. Okay. When someone comes in with a heart attack, for example, they have an acute interruption of blood flow and oxygen to their heart. Okay. What happens when you have no oxygen coming into your heart? You don't have enough NAD. PARP is activated within about 5 seconds. NAD is massively consumed and there's no ATP made. And because there's no ATP made, that heart muscle, which is at risk in the first few minutes, sadly, it goes on to die, to infarct. So if you maintain nad, you maintain ATP during the heart attack, you won't get the infarct and you won't die. So we made every effort, we designed drugs, and this is what I licensed to Genentech. By blocking PARP activation, it didn't consume the NAD during the heart attack. ATP levels were maintained and the heart did not get an infarct.

Wow.

Same with stroke. Stroke is the same way. A lot of these and I could go on and on and on. But PARP is very important in these acute events for aging. Though this is not done over minutes, this is a problem over decades. So the principles are the same, but it's not as dramatic.

So PARP is helpful because it repairs your genes. But if there's a traumatic event or an overactivation, it stops being useful for gene repair. And it causes all kinds of damage by stopping ATP.

So we showed this. If you take an animal or a person and you interrupt blood flow to their coronary arteries, so their heart is deprived of the oxygen it needs within about one to one and a half minutes, you get a massive influx of oxidants in that cell that attack the DNA. Attack your genes cause huge numbers of DNA single strand breaks, millions in the cell of the heart. Those activate PARP like crazy. Suddenly, PARP consumes NAD within about two to three minutes. If you measure the NAD levels in the heart after two to three minutes after a heart attack, zero, undetectable. And of course, you wait one more minute, no ATP, you wait another five minutes. Dead cell. So, yes, PARP overactivation in the acute setting is a killer.

Would it make sense to block PARP before you play a football game because you know you're going to get hit in the head?

That is something I never heard anybody suggest. It's a wild idea, but it's an interesting concept. We did prophylax animals many after Head. We did traumatic brain injury studies with parbac, and, yes, you can preserve brain function, reduce neuronal injury. I'm not suggesting anyone do this, but. Okay, okay, I'm with you.

If you're an MMA fighter or a professional football player, I have protocols for what to do before.

Before? No, it would help there.

Yes.

Yes. We have done dozens of studies in traumatic brain injury. We've done them in sheep, we've done them in mice and rats, and we have shown conclusively that you can ameliorate and prevent the sequelae of a concussive or a worse event. Yes, it is protective in that sense. Not making a recommendation, but it works.

No one that I'm aware of is using PARP drugs like the one you invented for this. And there may be side effects I don't even know about. But what I do know, having had a titanium knee to the head at high speed and gotten a brain injury, I'm fortunate that I know what to do for that. And I have a neuroscience clinic, so I was able to repair my brain. And as soon as we knew what happened, I started with the antioxidants and all. Yes, but the incidence of brain injury, even in kids or in highly functioning adults, you get in a car accident, you get whiplash, and it ruins marriages.

It. It messes with what's a major killer in the. And not just killer, but it leads to very sad situations where people have chronic brain injury that just doesn't get better.

I know. Six weeks after I took that knee to the head, I sent Tim Ferriss an angry email about something he didn't even do. Like, I was out of my mind. I was swearing all the time. And, like, what is going on? And some of this has to do with the fact that my brain, which actually, at the time especially didn't even have enough blood flow regularly, according to Amen clinics. And then I ran out of ATP for the parts where I scrambled my eggs, and so it took me a.

Little while to recover.

And the good news is we have neuroplasticity. You can recover.

Yes.

But I look at people who are at risk of these things and saying, all right, I know having ketones present reduces oxidative damage. There's all sorts of different strategies that are all mitochondrial enhancing. And when you peel all that stuff away, ultimately it seems like NAD is the most important of all of those.

It's the centerpiece, it's the major player.

Wow.

All right, so what about liposomal nad? I've seen some formulations of that.

Does that work? Well, there's liposomal NMN that's been looked at because people want to optimize the amount of NR or NMN that's coming in. I'm all for that, but it needs to be done in a way that's effective. So far, we haven't seen studies that really prove to me that liposomal NMN is better than just regular nmn. It might be, but I haven't seen the studies. I will say that liposomes are not easy to work with, having spent quite a bit of time with those. They leak. They leak over time. So there's stability issues even on the shelf. So it's a difficult modality to work with. More power to them that they should do great research and maybe that will improve it in the long run. But I haven't seen that yet.

Got it. And I realize I'm using big words if you're listening. Well, lipo, whatever. A liposome is a little. Call it a bubble of fat that you can use to put a pharmaceutical or a nutraceutical inside it. So it'll absorb through the gut lining or absorb into cells. So the very first liposomal glutathione on the market, I hope to bring that to market. Years and years ago. And then I had a dry liposomal bulletproof. And like you said, they're very hard to work with. My friends at Quicksilver make some cool stuff. There's even, like liposomal testosterone formulations and things now. So it's a cool delivery system. That's very finicky.

Finicky. That's the right word. Yeah. Difficult, unstable.

And what you have with the stuff you're doing at Wonderfeel is you're doing NMN plus you're blocking CD38 at the same time.

Right. We have two natural products, and they're ingredients, if you will, in our solution. One of them is resveratrol, which of course is from red grapes, and that has been. And it's in wine. Red wine. And that has been shown to block CD38. Very interesting. And the other is from olive oil, hydroxytyrosol. Okay. In the Mediterranean diet there. And that is also blocker of CD38. So that's why we took those two and we added those to NMN so that we would increase the supply, but we would block the depletion simultaneously.

You are the only person who's ever talked about hydroxytyrosol on the show. And I looked at a lot of the research around olive oil and there's plenty of evidence that says 30 grams of olive oil a day is good for you. Above that, it's a bit of a. It's a bit challenging. If you take a lot of oleic acid, the primary fat in there, it increases something called D5D and D6D, which means that your body way more easily oxidizes all the other Omega 6s. So olive oil. Good. Excessive olive oil drives oxidation.

Well, we don't provide olive oil. We just purify the hydroxy tyrosil.

Exactly right. So hydroxytyrosol is the most likely beneficial compound in olive oil. So when I put together one of my. I think it was my fat, my omega 3 formula back when I was at bulletproof. And, guys, I don't have anything to do with bulletproof. I don't. I don't believe they're following my formulas. I don't even track it. So, no. No commentary there I can offer you. But the thing I formulated years ago, I put hydroxy tyrosol on it. And my formulators are like, what is this? And I said, now there's a supplier. We got to do this because I wanted the benefits of drinking a gallon of olive oil. I just don't want to drink the olive oil because I don't think it's good for you at high doses. Right.

Hydroxytyrosol, of course, is an antioxidant, has lots of different functions. One of them is the CD38 blockade. But the antioxidant effect is also important. And to that end, by the way, we've added another ingredient in our wonder field, which is ergothioneine. So this is a natural amino acid. It's very, very powerful as an antioxidant. And the reason we did that was that we didn't want to have a lot of DNA damage. DNA damage activates parp. PARP consumes nad. So by giving that heavy hit with ergothioneine, we have a lot of antioxidant power in there now that reduces the amount of DNA damage and reduces the need for PARP to fix something which would consume nad. So all of this was focused on keeping NAD levels high, using antioxidants in conjunction with boosting the nad. Very important. And that's why it was necessary to include ergothioneine.

Ergothioneine is another one of these longevity molecules that most people haven't even heard of. And I look at this as. As foundational as glutathione. And when I started the whole biohacking Movement, including glutathione, was the rock star. And it still is. You need this for your liver, for your brain, inside all your cells. And orgathioneine is as potent via different mechanisms?

Yes, it is.

I think most people don't know about.

I should also add that glutathione, just to make a full circle here. Where does that come from? Glutathione is produced by a glutathione reductase. And the energy to make glutathione comes from NADPH through. And where's nadph? What is that? That's from nad. So NAD is acted on by NAD kinase. It makes nadph, which then creates glutathione, which is a major, major important antioxidant. If you take animals that can't make glutathione, they do not do well. Okay. And any kind of limited injury, even a minor, trivial injury, becomes a major problem. So glutath is one of the most important natural antioxidants that we have. And that's all dependent on having NAD there to make it. Without NAD you cannot make glutathione. Wow. Be very clear about that. Yeah. So NAD has a very important antioxidant functionality in that way.

One of the concerns that I've had, and this goes back to when I started in longevity, it was actually the late 90s where I'm in my 20s and I'm learning from people in their 80s and we were taking a lot of antioxidants, sort of like oxidation's the devil. And problem is we have this ox redox reaction that makes ATP. How do we know that when we take wonderfeel and now we're getting ergothioneine and we're getting resveratrol and we're getting all the other antioxidants like hydroxy tyrosol. How do we know that we're not suppressing oxidation to the point that it's a problem?

You do need some redox stress. It's very important in terms of signaling. We were the first to show that oxyradical signaling is very important in terms of the anti inflammatory effect in cells. I published that in 1995 when I was at Children's in Cincinnati. So yes, oxy radical signaling is important. You need a limited amount of redox stress, of oxidant stress. Too much, of course, causes all these other problems. How do we know that we're not giving too many antioxidants? Well, we listen to our customers. We have a registry where every single person who Takes our product, writes back to us. And most of them do because they're repeat customers. We don't really advertise, we don't need to. People like the product, they come back, they buy more. And so they generously give us their thoughts and their feedback. And we've seen no evidence of any kind of toxicity or any evidence of a problem with the material of the solution that would get us concerned. We're always watching, though. We have a respect for listening to the patients, to the customers. So if we do see any problem, we would quickly investigate that. So far we haven't seen that. What we do see are numerous reports coming back that exemplify just how effective this is. And it's really surprised me. I was a little bit cynical before about supplements. I was in the pharmaceutical industry, so I was on the bad side, right? So I was kind of suspicious, what are these guys doing? But when you read these reports, you have to stand up and pay attention. We had a 60 year old person with arthritis. She used to be a tennis player. She could hardly get off her couch and she's back and she's playing tennis now. We had a 75 year old lady who unfortunately had pretty advanced vascular dementia. Her husband was having to take care of her. She loved to do crossword puzzles. Before all of this, she was doing maybe one every day or two. She's now doing four a day. Her husband's crazy. He's the one buying it. IT Sexual health. All of the nitric oxide metabolism in sexual health is driven by the need to have NADPH activate EC nos. So we found people, both men and women. We had a woman who was 61 who was reporting much stronger orgasms and vaginal lubrication. We published, we're the first to publish on vaginal lubrication. I did that in 2004, showing that this whole mechanism causes increased blood flow to the vagina and increased lubrication. And that's entirely dependent on NAD being there.

So NAD drives sexual function?

Oh, yes. Erectile dysfunction is based on EC Nox. Look at Viagra. What does Viagra do? It prevents the breakdown, okay, of cyclic gmp. But what is making cyclic gmp? Nitric oxide. What makes nitric oxide? Nitric oxide is formed by the activity of the ECNO synthase, the nitric oxide synthase, that enzyme which is present in the cavernosa of the penis. That enzyme requires NADPH in order to work the electron which comes onto nitrogen to make nitric oxide. That literally comes from nadph. Well, NADPH is formed from nad. So if you have NAD deficiency, you can take all the Viagra you want in the world. It will not help.

No kidding.

No. Viagra is great if you're making nitric oxide because it prevents the cyclic GMP from being wiped out. If you don't have nitric oxide, forget it. The Viagra just doesn't work. And we know that Viagra works in maybe half the population that needs help. It doesn't work in everybody because some people cannot make nitric oxide.

Wow.

So this NAD is interesting because it will facilitate making nitric oxide. So it'd be very interesting actually to look at our product in conjunction with Viagra. We haven't done that yet, but the reports we're getting of sexual health from our customers suggest that something important is going on and that deserves more attention.

This is fascinating. One of the longevity pharmaceuticals that I take is low dose cialis. I take 5 milligrams most days. Right. And this isn't for sexual function, it's for vascular function. Because I don't want to get Alzheimer's disease and because I like having veins, it works very, very well.

Low levels of nitric oxide are absolutely essential to the preservation of your vascular system in several ways. First of all, nitric oxide causes vasodilatation not just of the large vessels, but of the microvessels. The micro vessels are what nourish the intestine, the gut, the liver, and especially the brain. You have to have good, healthy blood flow. As we get older, we get calcifications and other changes. The vessels get stiffer. So you need low levels of no, okay, in order to maintain your health. So NO is very important in the entire vascular, is that nitric oxide. It inhibits platelet activation by increasing the cyclic GMP in the platelets. So platelets are great. If you get a cut, you don't want to bleed, you need your platelets. But platelets can also adhere to to the vessels, especially in the heart and in the brain, that can cause a stroke or a myocardial infarction. So you don't want excessive platelet activation. That happens as we get older. Again, nitric oxide is key in keeping the platelets quiescent, keeping them happy and non activated. So again, nad, by facilitating NO expression, is critical to vascular health. And that's been shown now even in clinical studies with NMN supplementation. They've shown, for example, an improvement in blood pressure. In fact, if you remove CD38, which as I mentioned, breaks down NAD, so you have more NAD, you see a Fall in blood pressure.

Interesting.

Yeah. So nitric oxide, CD38, NAD, they're all connected, but the centerpiece is NAD.

Have you seen people's blood pressure drop when they.

Yes, it's in the study. Okay, yes, that's been shown. Now, if you take people who are on heavy NMN supplementation, the Buck Institute of Aging and a number of the NIH places have recommended 900 milligrams total per day. Some of the studies have used much less, and they haven't seen as good results. There was one study with 250. Yes, there was a study with 250 milligrams in patients. They had an inkling of something good happening, but it was not the right dose. But when you get to the right dose, you can see changes that are favorable, not only in blood pressure falling, but you get better insulin sensitivity, so less diabetes. All of these things are happening because NAD levels are rising to the level where they can produce nitric oxide and relax the blood vessel and provide a defense against oxidant stress in the blood vessel.

If someone is at normal blood pressure and they increase their NAD levels, is it going to drop even further?

No, it wouldn't do that excessively. But when you measure your blood pressure with a cuff on your arm, you're looking at. You're not looking at blood flow, you're looking at blood pressure. What we really care about is not really just the pressure. We're looking at the blood getting to where it's supposed to go. And that can happen in a number of ways with nad. First of all, as it opens up the small blood vessels, it allows it to go everywhere capillaries. But in the longer term, nad, higher levels of NAD increase mitochondrial supply, and the blood vessels therefore are able to enlarge in form. So a person like a basketball player, someone who's out there going back and forth on the court, he has far more mitochondria than I do. And that's because he's been exercising. He has NAD being produced. You get more mitochondria. So in the long run, not only does it help your immediate health, but it makes you in better shape. You actually condition a runner will have much more blood supply throughout his muscles because of this NAD increase.

It makes so much sense. There are about 30 million people in the US alone who have COVID vaccine injury, also known as long Covid. Yes, I know, I just trolled a bunch of people with that. But what's the role of NAD in long Covid?

Actually, there was a study looking at the Effect of NMN in people who had had Covid in terms of their vascular function. And it actually was much better. So that's a population that is at risk. People who've had the vascular vaccine or Covid, you know, they've had the spike protein, the vaccine has the spike protein, Covid has the spike protein. So that is an activator of endothelial damage potentially. And so no and NAD will protect the blood vessels. So if you've got Covid, it's recommended from this article. It's an NIH publication. It's something to think about. And certainly if you have long Covid, it's something also to think about.

I had chronic fatigue syndrome and fibromyalgia diagnosed in my 20s. Those are exactly the same thing thing as long Covid. Now, you can have different things that trigger the whole cascade of mast cells and all the stuff that's involved in those. So this has been an area where I was able to recover from that. And I did get Covid and did not get long Covid because I take care of my mitochondria. So I look at all those conditions as mitochondrial and inflammatory things. And if you want to turn off inflammation, you turn on mitochondria. And as you just explore, described NAD's most important. @ the same time, we used to.

Think about diseases as being sort of these isolated instances of bad luck. Oh, I got diabetes. Oh, my goodness. I got cancer. Oh, my gosh, I have fatty liver disease. Oh, I'm having a renal problem. Oh, I'm having Alzheimer's. And we had departments set up, and then we had doctors who had specialized their entire lives in each of these very distinct areas. And that's one way to look at medicine. But that's the 1950 ways to look today. We have to see these really as an integrated whole. Why do we get sicker as we get older? Is it just bad luck? No. The aging process is a core, fundamental derangement that then spawns injury in all these different organs. If you happen to have an injury in your knee, suddenly you have arthritis, but it's really not arthritis. Really. What it is, fundamentally, is aging. And so we can spend all our time trying to treat arthritis, or maybe we need to go upstream and spend our time thinking about the aging process itself.

I look at it like this. If I age, it's my fault. It means I haven't figured out what I could be doing or I could have done to do a better job of it. Right. We know all these different pathways, and maybe there's some things we don't know. Well, that means I haven't discovered them yet or you haven't discovered them yet.

That's right. And it's never too early. You know, a lot of people think that aging starts with when you're 60 and 70. They're elderly, right? You get your senior discount. I just got mine. I was so excited. Babe by day. But actually aging doesn't start when you're 65. Aging actually starts in your early 20s. I'm sorry to say that, but it's true. If you look at a baseball player, the rookies are great. 20 years old by the time they're 30, they're kind of not rookies. By the time they're 36, they can't run as fast, they can't dive, they can't slide as fast past. It's not the same person. So if you care if you're in your early 30s or in your late 20s and you want to maintain vigor, you're an ambitious person. You know, you want to master your skills, you want to exceed and you know, do everything you can in your. In your profession. Do really well there, succeed there. You want to have good pleasure in your life and good sexual health. It is not sensible to wait till you're 60 to 70 to wake up, wake up now when you're in your 20s, start thinking, what can I do to maintain my nad at a healthy level so that I don't develop these problems? I don't have to work backwards to fix them. Let's prevent them.

The reason that I called what I do biohacking is that I learned because I had the unfortunate problem of being old when I was young. The things that make old people young make young people powerful. And all of a sudden I think, what if I talk about it in a way I would have listened when I was 19?

Wow.

I get to choose to not be obese. I get to choose the skin I want. I get to choose the brain function I want. And as a side effect, you have way more stamina and you have a better life and you don't age the way everyone else does.

That's right. I mean, people in their 20s care really about three things. I would say they want to be mastering things, whether it's at work or in sports. They want to master things. They're ambitious, they have drive, they have energy. They want to flourish, whether it's in sports or whether it's at work. And they want to have fun. They want to have pleasure. They want to have a Good life, family, this is what. Well, all of these things will be derailed if you don't have an NAD level that can support you in your endeavors and your goals. I mean, you've got to be alert, you've got to be sharp at work, you've got to be. If you're on the tennis court, you got to win, you got to have muscle, you have to have power, you have to have pleasure and fun. You have to have a normal sexual life. So all of these things can be derailed, but you don't have to let that happen. You have a choice.

And it's funny. Alcohol is just a bad idea in general. And I wish I hadn't have drunk when I was in college, because I know now what it does. What is the role of alcohol and nad?

Well, alcohol first of all can spawn the generation of oxidant stress. It directly damages tissues with the alcohol because it gets into the membranes. But more than that, it can lead to a lot of oxidation oxidant injury. And so that damages DNA, activates parp, consumes nad. So NAD levels in an alcoholic are suboptimal. Best thing, of course, is to stop the alcohol. But over and above that, you want to maintain your levels of NAD in the face of alcoholism.

Got it.

The best thing is to stop the alcohol. That's the.

Do you drink?

I drink on Shabbat. I have a glass of wine.

Okay.

I limited as that.

Yeah, I, I have a rule. I drink if it's older than I am.

Okay.

So there's an economic reason to not drink. Right. So maybe once a year, I'll have, you know, good sake with sushi or something. But yeah, it's for me, not even a monthly thing because I'm into cognitive function, longevity, and I, I know what it does. And frankly, alcohol is just about the.

Worst thing you can do for brain function. It just is. It's a neuronal injurious agent, pure and simple.

My experience is a long time Burning man guy, and I have a ketamine as an offering through a medical doctor up at my neuroscience clinic. In fact, a lot of my new book, I have a big section on psychedelics. Any psychedelic journey or deep meditation or breath work, it doesn't really matter what's getting you into these altered states. Yeah, if you can upregulate mitochondrial function, you have a much deeper, more powerful experience. And it follows then that having adequate nad, when you're calling on the brain to go into these altered states, whether they're self induced or chemically Induced. It's a very, very big difference in the quality and intensity of the experience.

Well, we know that. I mean, now I'm thinking about it in light of what you're saying there. The psychedelics upregulate in a very acute fashion the metabolic activity of the brain. And the brain actually is the most metabolically active organ in our body. It uses 20, 55% of our blood supply. The oxygen demand by the brain outstrips everything, including the heart. So anything that you can do that, anything that you are doing that causes increased brain activity and function will require a commensurate amount of oxygen to support that and nad. So I guess if this psychedelic experience you're describing is energy demanding, then it's obligatory that you have sufficient NAD to support that.

So when I'm going to go on a journey, and because I'm not recommending any of this stuff, I'm just talking about my practice and what I've found works best. I want to have some ketones present and I don't care if it's from MCT or ketone dials, which are, I think my preferred way to do that at this point. And human makes out hbmn and then I take a bunch of mitochondrial enhancers and wonder, feel, of course, because what you want is for every cell in your body to be able to do, do everything that it's capable of doing effortlessly. Because there's this beautiful thing that, that I've noticed in biology. I'm a distributed systems computer hacker guy and like, well, if you don't have enough compute power, you stop doing some things that aren't critical. And the body is the same thing. If I don't have enough metabolic power in the form of nad, ATP, mitochondrial function, well, what are the things that aren't necessary to be alive right now? Let's not do those. So if I can stack all of my energy metabolism and all of my antioxidant metabolism to their fullest than when I'm doing something, whether it's an athletic thing or it's a spiritual journey kind of thing, then I'm going to have the full experience and my body will come off.

I want to add something there because there is a positive feedback loop, which of course you being a computer engineer, you know what I'm talking about. When you are in a situation where you have a fall in the amount of NAD and systems start to go awry, those will actually increase the damage in the gut that allows leakiness, which increases CD38, which further lowers NAD. So it is a positive feedback loop in the bad way. It gets worse and worse and worse. In contrast, if you can do the proper things in terms of your health and maintain nad, you will have a positive feedback loop in the other direction in terms of restoration and prevention of disease. So it's a very highly amplified system. It's sensitive if you are taking, say any NMN supplements or our product, for example, and all is going well. And we've had all of these people comment about how their lives have changed. We've had several people who went traveling and forgot their stuff. Now those people seem to regress pretty quickly after about two to three weeks. So it can get better quickly, but it can get, get worse if you're not doing these right things. So it's the sort of thing where you need to be mindful to do it every day. I mean, this is a journey. Longevity treatments are not something you can do now and then if you're committed to taking care of your health. It's something that you got to do every day. We recommend, for example, that our capsules taken at the time you brush your teeth because you remember that in the morning and you, you want to do this every day. All of these things you're discussing, we're talking about here today, require commitment. It's something, it's lifelong. If you want to make a difference, you have to maintain that momentum and you can't be skipping out. You got to be consistent.

You saw my supplement room?

Yes.

Where I take about 150 pills a day.

I never saw anything like this before.

I've been doing this for 20 plus years.

Wow.

Because just hanging out with people in their 80s when I was in my 20s, I know what's possible. And also because I was pretty sick at the beginning of this and the benefits keep coming in where I'm not slowing down, my brain works.

Look, the evidence is out there for us to see. We all know people. My mother, for example, God bless Her, she's 92 and a half. Her house burnt down last week. Oh no. But, but, but she ran out of the house and she's all ready to rebuild the new house. She's excited, she can't wait. Right? That's a 92 year old with energy, with activity, with drive. But I know a lot of other people the same age and they're shuffling, they can hardly walk, they have limited activity. My mother's out there running down buses to go to the symphony, go to the museum. And other people, they need care, they're at home. So 92 is not 92. 92 is just a number. If you want to maintain your health and you're good about this, you can be a very vigorous, active citizen well into your 90s, maybe longer.

Wow.

But it requires a lifelong commitment to stay in good health and some good genes. That doesn't hurt.

Genes do not hurt.

Yeah.

How much wonderful does your mom take?

She doesn't take it yet.

She doesn't. And she's just naturally doing this.

Well. All her relatives live to be 100. I'm sure her PARP activity is probably off the wall compared to most people. So she's not getting these genetic damage accumulations. But, you know, not all of us have that. We all know people who live to be very old, but there are a lot of people who are in their 60s. Frankly, they look like they're 80 or 90. I have friends like that. They're not doing anything wrong, they feel. But really, they could be doing more. They could prevent this.

What are the biggest mistakes that people make with NAD supplements?

I think that just taking an NMN or an NR supplement by itself is a good first step, but I think the mistake is not recognizing that depletion of the material is just as important as its supply. I really believe in the concept of combination therapy, so I think I wouldn't call it a mistake. I'd recognize that things like CD38 over activation are going to cause a problem. So I think that's very important. Second thing is consistency. Like I said, the same. This is not occasional, let me try some supplement. It's a commitment. So that's a mistake if you don't maintain that reliability and compliance and take it every day. Other mistakes, they are not recognizing that the NAD story is part of a systems biology thing. You have to exercise, you have to keep your weight down. You have to be doing all the other important things with your diet and all the important things with your nutrition and taking care of yourself. So it's part of a program. It is not a solution by itself.

What do we know about NAD and the brain?

Well, there are studies actually looking very carefully at this and clinical studies even showing that NMN supplementation or NR supplementation have a real effect on memory, on the rapidity of your thinking. They get rid of brain fog. They allow you to be sharper. All of the things that you would expect from a molecule that is at the centerpiece of the energy of the brain. I mean, the brain is a motor. It's like a computer. It runs on. It doesn't run on electricity? Well, it does run on electricity, actually, but it has power. And if you strip the power away, you turn it down 50%, what do you expect? You're not going to be sharp. So NAD is absolutely front and center. In fact, it is the organ most demanding of nad. Why do I say that? If you lose, if you have a traumatic brain injury or a stroke, or there's any kind of interruption to blood flow in the brain, you had eight minutes.

Wow, that's it.

Eight minutes go by without oxygen, you have irreversible neuronal injury and severe brain injury. So there is no time and no tolerance for a lack of nad. Minutes are life threatening. So great that you brought that up. The most important organ in the body dependent on nad.

Are there synergies between NAD and coffee? Or caffeine, my favorite biochemical?

Well, caffeine is a stimulant and it's going to activate the metabolism of cells. And by. When I say activate, what does that mean? It means that it increases the energy production and consumption in the cell. It's like being in a car driving 20 miles an hour or 100 miles an hour. When you drive 100 miles an hour, your car engine is working like crazy, you're using more gas, you're going faster. All of those things happen when you take caffeine. So your need for NAD in those situations is heightened. If you take caffeine and you don't have the NAD that you should have, you will have a relative deficiency and it could probably cause you some harm. So if you're going to be a heavy coffee drinker, make sure that you're youthful in your cells and that you have your NAD maintained.

We know there's dozens of studies now associating coffee consumption, not necessarily caffeine, but coffee consumption with longer life. And I think some of that is because of the antioxidants that are present in the coffee. But if you were to stack those with ergothioneine and the other compounds you have in Wonderfield and you have adequate nad, you're going to get more benefits. And I think either one by themselves, work the combination together. Seems like a better idea.

Yes. We're actually doing research in this area right now because we think that adding a stimulant to our products may be important. Not in the long run, but in the short term. It allows you to be sharper, faster, better during the day. Everybody wants that. If you're an ambitious young guy or girl, you want to be full of energy and do what you need. To do. But at the same time, we know that, like you said, stimulation without the commensurate increases in energy supply is asking for trouble. So that's why we're thinking about a further combination therapy like that.

What does NAD do for ketosis?

Well, fat metabolism is a. Of course, ketones are produced when fat is metabolized, right? And when fat is metabolized, that requires energy. Okay. Because the process of beta oxidation of fats, that's how fats are removed in adipocytes in the fat cells. It's an energetic process when insulin isn't present. And that process requires energy in order to process the processing of fats, in order to degrade them. So when you are ketotic, because you're breaking down fats, you need energy to facilitate that process.

So energy, NAD can help with breaking down fat, so you can be in ketosis.

The other thing to keep in mind is that NAD is very important in the Krebs cycle. Okay. There are two molecules of NAD which enter into the Krebs cycle, and the Krebs cycle is using ketones and incorporating them. So it is a very central part of intermediary metabolism. So, yes, you do need to have good NAD levels when you're ketotic.

There are a lot of different longevity patterns, pathways that we cover on the show, and I'm trying to manage all of them for myself. We have things like mtor, ampk, and sirtuins. How does NAD compare to each of those?

Well, the NAD and the sirtuins, of course, are related because sirtuins use nad, they use it to ribosylate proteins, which causes deacetylation. So sirtuins and NAD are intrinsically connected with each other for other pathways. All of them will interact with metabolic machinery and oxygen flux, and all of these things more or less depending on the specifics. So I don't know. I can't answer that generally. But on the specifics, yes, there will be research that we are doing and other people are doing to make those connections.

The MTOR front is really fascinating to me because for listeners, MTOR causes tissue growth, which is good, unless it's on all the time, in which case you might get cancer. So what I like to do is, is suppress my mtor, because the more you suppress it, then the stronger it rebounds. So the three things that we know suppress it are, let's see, coffee suppresses mtor, exercise suppresses mtor, and fasting suppresses mtor. So the tripling down on MTOR thing as well, wake up in the morning, have some coffee, don't eat breakfast, exercise. And at that point you've smashed MTOR down and then you have some protein and some carbs which raise mtor. So then you get a big surge right. When you want to put on muscle after the exercise. But if you want to put on muscle and you don't have enough metabolic energy because you're low on nad, you simply won't be able to put on muscle. You just get the systemic stress of all that behavior. Behavior. But you can't adapt to it. You gotta have your minerals, you gotta have your, your substrate in the cells to be able to do this. And that means you're getting more results and less time from the exercise. So there might not be a study, but mechanistically we know if you're gonna build any protein in the body, what's powering that? It's NAD through ATP, right?

That's right. When you're weightlifting or when you're doing any kind of regular exercise, there's a period of stress where your muscles are undergoing hypoxia. They're not getting enough oxygen because you're vigorously exercising, lifting weights, whatever. And that is a stimulus for growth of new muscle, for growth of new protein, and for fission and production by fission. I mean separate reproduction of mitochondria. Right. So someone who's an active runner or a weightlifter or a bicycler is causing stress to his system during the activity. And then when he, he waits a day or two before he does it again, during that time there's regrowth and new growth of muscle. All of that requires an incredible amount of energy in order to facilitate protein production. Protein synthesis is a highly energy dependent process. So you've got to have adequate levels of ATP and NAD to sustain and support that. So that is why the good nutrition is critical. To have the ingredients for protein, you need amino acids, you need to have the right diet, but then you have to have a steady state level maintained of NAD in your cell to facilitate the expansion of the muscle.

Wow. What do you know about NAD and willpower?

I mean, in terms of your mind, in terms of your energy. I've never explored. That's a great question.

Can I share something with you? This is my favorite study maybe of all the studies ever. And I wrote about this in my brain enhancement book. And it's a study from Israel, where you live. And a group of scientists got together and they said, what predicts whether someone's going to get parole to get out of prison? Is it their Gender, is it, their race, is it, where they're from, socioeconomic, what crime they committed, all of that. And after they comb through the data, what predicts whether you get parole or you get sent back to prison is what time is your meeting with parole board? Because decisions take mitochondrial energy. So in the morning, if you get your meeting, you're very likely to get out because they'll consider your case, okay, you can go. And if they're tired at the end.

Of the day, blood sugar levels are.

Lower, mitochondrial activity is lower, brain function is lower. It's just too much work to think about it. Stay in prison. And there was a brief spike right after lunch when their blood sugar peaked and then dropped again. And you're screwed if you have an afternoon meaning. And so I found the studies, there was two studies that directly associate mitochondrial function with willpower, which only makes sense because this drives everything.

Well, I think that the whole issue about NAD level being susceptible both to or influenced both by supply and depletion is important. If you take a supplement in the morning, and this has been shown in animals as well as in humans, when you take a supplement, you will get a boost in your blood levels of NAD and nmn. It goes up, but it's not going to stay up because over time, the activity of CD38 on the outside of these cells will chew it up as well as it being used up. So that is why we feel so important. It's so important to have this combination so that you have a sustainable level of NAD throughout the day, and it's not just a brief burst or episode in the morning after you've taken the supplement.

So this would be wonderful in the morning and at lunch.

No, you take it once a day. But by blocking CD38 activation, by inhibiting CD38, you prevent the subsequent breakdown that would occur later in the day. So think of it as a bathtub. You have water going in and you have a drain with water going out. You can fill up the bathtub in the morning, but if there's a big hole in it during the day, it's going to run down. The only way to maintain a steady state level of something is to make sure that the water going in is good and at the hole, letting it out is small.

Right.

And this is the point of having that combination. That's why I think you'd have a more sustainable level when you're blocking CD38 and not just giving the supplement moment.

That makes so much sense. The other process that's driven by mitochondria is the glymphatic system, which is something that happens when you're asleep at night. And your brain basically washes itself out via a recently, a recently discovered mechanism. And I did find a couple studies showing that that's also derived from mitochondrial things. You have to pump this stuff out. And this isn't the kind of pumping that happens when you walk, it's a of kind of pumping that happens when you're asleep. Is there a case for increasing NAD for sleep efficiency?

We have had, and not just we, many people have commented that NAD supplementation has a very profound effect on the quality of sleep. We have seen this from our customers, many anecdotes. This is one of the most common things that come back. But not just us. There are numerous reports with NAD supplements like the NMN and NR commenting on exactly, exactly this point. I don't know why that is the case. We don't, I mean, there's very little research really on the type of energy requirement during sleep and where and how it's done. But let's face it, sleep is a process which is removing adenosine. That's one of the main, I mean it does many things. There's neuronal plasticity, there's incorporation of events into long term memory. But fundamentally, during the day, the brain, like any organ, is having to consume energy in order to do its job. And as a consequence of that, the brain is accumulating metabolites of ATP that break down. It uses ATP to make it go. The ATP becomes ADP and AMP and ultimately adenosine. So when that all happens, by the end of the day, say 10, 11 o' clock at night, you're, your brain is chock full of adenosine. It's exhausted, to put it in another way, during the night. And the adenosine, by the way, is what makes you sleepy. And that's why coffee keeps you awake. Because coffee is an antagonist of the receptor of adenosine. So a person who takes coffee and takes caffeine doesn't allow the adenosine within their brain to make them sleepy. Adenosine says to you, I'm sleepy, go to sleep. Okay. So when you start to go to sleep, the adenosine is then taken up into the cells and ATP with help of NAD regenerates the ATP for the next day. When you wake up in the morning, you're feeling pretty good, your adenosine levels are low, your brain is full of ATP, you're ready to think, you're ready to act. So NAD during the night is the key driver of the process, which is restoring your ATP levels and lowering your adenosine. So you're using NAD at night to get back to where you were for the next morning.

You always take Wonderfeel in the morning.

We take it in the morning.

What happens if you take it at night?

Well, it probably would be okay, but think about it. You're going to have some type of burst of activity or levels. I mean, when you take any molecule, whether it's a drug or a supplement, whatever, you take it in the morning at 8 o', clock, your peak level will typically occur between 30 minutes and 2 hours. And almost all drugs, there are a few exceptions, but most take Tylenol for example, 15 to 20 minute peak, Advil, 30 minute peak. So when you take Wonderfeel in the morning, you're going to get your peak early. When you want to have the highest levels because you're moving around, you're active, you're going to work, you're bicycling, you're thinking a lot. So you want to have super high, high levels. Right. Then to take it right before you go to sleep seems like kind of a waste of time. You need a steady state level while you're sleeping, but you don't need a big burst. You're not doing a huge amount of activity when you're sleeping.

In general, one of the things that, that a lot of humans will do is if something's good for you, more is better. I believe this about exercise. I, for 18 months I worked out 90 minutes a day, six days a week religiously. I never lost a pound because I was over training and under recovering.

Right, right.

Is there such a thing as having too much NAD because you're just popping supplements all the time?

Well, there have been studies of this going up to 900 milligrams a day. And about four or five studies now have all shown that the best effects were at 900 milligrams. There was one study that showed also a good effect at 600 milligrams, but slightly better at 900. And there is actually courtesy of Dr. Sinclair's study of where he actually went up to grams, several grams. He claims in that study that no one was hurt, which is good. It means there's a nice safety factor so we can all step back and relax a bit. Whether you need more than 900 milligrams to be effective has not been examined. There has not been a careful comparison between 900 milligrams and 2 grams. It might be Better at some point, though. Having said that, too much of something may not be a good thing. And all of the. When you think about biology as a whole and the way our system works, the entire organism in the human biology, in any kind of biology, is based on having the foot on the gas and the foot on the brake simultaneously. This is how we create control. We don't have a system where just the gas is on or just the brake is. So you need to have. Have a certain amount of something, but if it becomes grossly excessive, you're going to have other factors involved. If NAD is spinning the Krebs cycle too fast, that could create byproducts that can't be handled. So there could be a lot of things where excessive NAD is not needed, certainly, and could actually be injurious.

Okay, so you like the recommended dose, and that doesn't change.

For the moment, there should be research examining all doses, but this is where the research currently tells us it's best. Okay.

Anecdotally, I did notice, especially with nr, which I started taking a long time ago, I felt a difference at 2 grams. I didn't feel at a gram or less. But especially in the early days, that stuff was really expensive. It was like $500 a month to take that much, which is kind of absurd for most.

Keep in mind that when you're taking nr, you're going to get a boost. Yeah, but then it's going to come down because of the CD38.

And we didn't know the CD38. You hadn't done all the research. And so these are old days. So maybe now the lower dose with blocking CD38 is.

And I want to emphasize that at Wonderfield at least, and just in my life, I'm a deep believer in the importance of doing research. I don't just like to recommend something or even think about it. My entire career has been based on researching everything. I'm not just curious, but it can help people. People. And we, we need to do these studies. So this whole health area with nad, I'm telling you what I know today. I hope we'll know a lot more next year. And that'll be from research.

Well, thank you for.

We're carrying out that research, by the way. We have a big biology lab where we conduct research activities constantly at the cellular level, at the animal level. We're asking questions about this all the time.

Well, thanks for your relentless curiosity. That's what it takes to really discover this. Instead of just deciding something works and then sticking to your Guns.

Yeah.

I have a final question for you as we wrap up the interview. And you've studied all the different biochemistry, you've treated people in hospitals. Is there a hard truth about biological aging that even biohackers wouldn't want to accept?

I don't think that pessimism or cynicism or resignation, capitulation is appropriate for people. If you just look historically where we were 200 years ago, where very few people live beyond the age of 49, if we go back 5,000 years ago, where very few people lived ever beyond the age of 25, all I see are good things happening. And I don't think just like the four minute mile. You know, there was that whole debate before Roger Bannister ran and they asked him afterwards, did you think there was a physical impossibility to run a four minute mile? He said, no, I just had to work hard to train. So I don't think there is a barrier as long as we are wedded to the commitment to do the research to understand why we're aging. We need to do a lot of research. But I am gung ho. I'm ready to be part of that research. And I think the sky's the limit. We just have to, to. We have to push hard, be optimistic.

Well, Dr. Andy Salzman, thanks for your lifetime of just incredible work and going out there and saying, how do I do stuff that affects more people? I think you've had a meaningful impact on our understanding of biology and aging and cell metabolism and a bunch of other stuff, cancer. So you had an impact and I love it that you're not slowing down.

So I appreciate, it was a pleasure to be here. Thank you.

You guys, wonderfeel.com is where you can learn about all this stuff and a lot of your writing is on that web page as well. Or you can just read his 170 publications if you want to.

There's, there's that.

If you like this episode, you know what to do. Have more NAD in your life. It seems like that's a good strategy. It's not the first time you've heard it on the show, but this is the first time we've gone deep on CD38, ergothioneine and hydroxy tyrosol. So this is a good combination. And as you know, if you listen to the show for the last 10 plus years, I take 150 supplements a day and they're carefully designed for my metabolism. I don't publish the entire list because if you did what I did, you'd probably get disaster pants, or as my daughter calls it, underwear surprise. So you want to figure out what is the load on your life? What kind of stress are you under? What kind of aging do you want to have? What kind of power do you want to have in your. In your brain right now? And you try things, say, I'm going to try Wonderfeel. So you try it for, I would say, at least three months and see what happens. And we're great at understanding I felt good today, I felt good tomorrow. But some of these effects build up over the course of weeks, and we're terrible as a species at noticing effects that are just down downstream. So this is one of those things. Get your NAD up and your CD 38 down and just watch what happens over time. And you might say, I've always felt this good. And then let's say you stop it for a month and you go, oh, look, my aura ring. Or in this case not my ultra human ring. I'm wearing both. It says, oh, wow, my heart rate variability started to drop. I didn't get as much sleep. My morning readiness score isn't where it was. And you realize, oh, there's these gentle patterns that happen over time. And you want to live a very long time like I do. You want to watch those as well. And there's so much evidence at this point, this is probably the 10th episode on NAD and the first one to go in this level, that this should be a part of your longevity strategy. And maybe say, I can't live longer. I'm a Peter Attia fan who believes you can't extend human life. That's okay. You can still improve human progress, performance, and the quality of your health span if that's your only goal. I think your goal should be lifespan plus health span, and that's my goal. So if you share that, get your entity levels up via any means necessary. Thanks for listening. See you next time on the Human Upgrade Podcast.

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