← The Neuro Experience
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- [00:00]
A
A lot of people don't realize is that high energy electrons run all living things.
- [00:05]
B
You've just described a three part pathway. You've got nmn, nad, ATP, NMN doesn't go into cells. Didn't they just recall this a few months ago?
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A
All fresh food has NAD precursors. Because like I said at the very, very beginning, NAD is the electron carrier in all of life.
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B
Charles.
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A
Louisa.
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B
How are you?
- [00:28]
A
I'm very well, thanks.
- [00:30]
B
We've, I've been following you for a long time, so I'm super excited about this. Your space intrigues me, albeit, you know, in the neurology space. I'm now going deep into the longevity space and been following along your tweets and your wonderful threads and I'm really intrigued by them.
- [00:51]
A
Good, good.
- [00:51]
B
And I'm sure the audience is too.
- [00:53]
A
Great.
- [00:54]
B
So why don't we. I first want to understand how you even got into the field of metabolism and understand what intrigued you about this area.
- [01:04]
A
Well, I guess I've been working as a professional, you know, molecular biologist for 40 years. That's the short answer. I can give you the, the whole, the whole path if you want.
- [01:17]
B
I'm excited.
- [01:19]
A
Let's see. So I'm 61, I'm going to be 62 in a couple months. Graduated from college in 1983 with a degree in biology. Moved to California from Connecticut and worked in biotech for five years in a couple of different companies. And then I moved to stanford. Got my PhD in Stanford in the cancer biology program, biochemistry department. I was working on prohormone processing. So back in the day, in the late 80s, late 80s, early 90s, when I was working on it, nobody knew what was the enzyme in our cells that's responsible for processing Insulin. Right. You know that insulin is made from a precursor molecule, right? Turns into an A chain and a B chain, the C peptide is released, right? All that stuff. So there's a cutting enzyme called a protease and we actually purified that protease, we purify the yeast form of that protease, but it's essentially the same enzyme as humans have. So that's what I, I got my PhD for 1993, had my PhD, spent 10 years in Northern California, decided to go back to Boston. In my field, you're not considered a fully formed scientist with a PhD. Believe it or not. You know this. So did postdoctoral training at Brandeis. And there I added X ray crystallography to the things that I do. I was funded by the Leukemia Society at Brandeis for 3 year postdoc, started working on a family of enzymes that have to do with nucleotides, you know, like the building blocks of DNA and RNA building blocks of nad. NAD is a nucleotide itself. And so I had a successful postdoc, got my first faculty position in 1996, really focusing on these nucleotide binding proteins and nucleotide related enzymes. And in my first six or seven years as an independent faculty member, I ran into NAD. I ran into NAD, the central catalyst of metabolism. And let's see, 96 to 2003, I was in Philly at Thomas Jefferson University. 2003, I moved to Dartmouth College, Dartmouth Medical School. And that's where I really kind of blew open the NAD thing.
- [04:24]
B
Seemed more exciting than the cancer biology.
- [04:26]
A
Well, you know, to me, I, you know, my current title at City of Hope, I skipped a little bit there. There's some exciting stuff in the last 20 years, since the 2003 when I moved to Dartmouth. But right, right now I'm a chair of a department called Diabetes and Cancer Metabolism. So NAD relates to cancer, NAD relates to diabetes and obesity, it relates to rare diseases, it relates to mitochondrial diseases, it relates to health, it relates to neurodegeneration, it relates to heart failure. NAD is probably, we should say what NAD is.
- [05:13]
B
Well, I was going to. Yeah, because metabolism and metabolic health being the central theme of this entire episode and being the central theme of neurodegeneration and longevity. Why don't we tap into that?
- [05:26]
A
Okay. We'll do the last 20 years at some point. Yeah, but so, all right, I, I drove here in an electric vehicle, and you'll see where I'm going in a minute here. But most people have an idea of what's inside an electric vehicle, which is a huge battery. Right. And then a lot of moving parts. So you have transmission, you have a steering wheel, you have a cooling system, you have an entertainment system, you have a braking system. All of those things require electrical power. They require power. And the power is transmitted on copper wires. And you push the button and you have current and you could deliver, you know, high energy electrons to all of those different components. So what a lot of people don't realize is that high energy electrons run all living things, not just electric cars, but high energy electrons run plants and animals and fungi and bacteria and everything else. And the energy from high energy, that the energy in the high energy electrons actually comes from the sun. We could go into that if you want, but it basically is captured onto something called nad. So in metabolism, we have protein Fat and carbohydrate, which are the three macronutrients that from which we derive our calories. Right. Which is another kind of energy conversion unit. And in the, in the course of burning that fuel, you know, we capture high energy electrons onto a molecule called nad. And when the electrons are captured, the form of NAD is called nadh. Right. At the inner mitochondrial membrane, the NADH electrons initiate the electron transfer chain that generates ATP. That generates most of the ATP in our bodies, in our skeletal muscle and our heart, you generate phosphocreatine, which allows us to have the actin myosin, you know, gymnastics and, you know, power our muscles and power, you know, blood circulation. But ATP is required for, you know, virtually all of the energy dependent steps in metabolism. It's required for us to transmit, you know, ideas, it's required for us to record memories, it's required for us to have emotions, it's required for us to do repair reactions. So that's how central NAD is. Nad. Nadh is centrally involved in cellular bioenergetics, converting our food into energy. Right. And then there's actually two other NAD coenzymes that a lot of people don't even mention, but they're called NADP and nadph. Right. And they're required for anabolic reactions. So they're required without oxygen. Well, no, anabolic means making stuff like building stuff. We use the term anabolic steroids. That means a hormonal system that's involved in making things. So we have to make our own lipids. Right. We make the bulk lipids for, you know, cell membranes. Right. If you repair cells, you have to make cell membrane. You're turning over RNA all the time. You have to replicate DNA, so you have to make DNA, RNA protein and lipids. Right. All of those reactions require electrons on nadph.
- [09:47]
B
Okay.
- [09:48]
A
And there's also detoxifying reactive oxygen species depends on electrons on nadph. So what our group has discovered, really, we're known for two things. So shortly after the move to Dartmouth, when I realize that there are a lot of unsolved problems in NAD synthesis, even though NAD was a classically known nucleotide and classically known as the carrier of high energy electrons, I started realizing around 2003-2004 that there was a very good possibility that there was another way of making NAD that hadn't been been investigated yet. So I discovered the nicotinamide riboside kinase pathway, so discovered the vitamin activity of nr and my postdoc. And I, Pavel Biagnowski and I Discovered the identity of the nicotinamide riboside kinase genes and the nicotinamide riboside kinase enzymes that are used to convert NR into NMN and subsequently NAD coenzyme. So we're known for this NR pathway.
- [11:16]
B
NR being the precursor, NR being.
- [11:19]
A
It's actually the biggest piece of NAD that can get into a cell and replenish NAD coenzymes, right? Now, the other thing that our group is known for is we developed a technology called quantitative NAD metabolomics. It's a lot of syllables. I'm sorry, but you know about genomics, right? So with genomics, we can sequence anything that we want, right? Chris Mason, maybe someday. He's in New York. You can interview Chris, and he goes around, like, swabbing subways and going to various places and sequencing all kinds of organisms, right? Sequence bacteria off of, you know, you can imagine subway seats and, you know, so you can sequence anything, right? You sequence us. You can sequence, you know, tumors, you can sequence tumor evolution, you can sequence novel coronaviruses, you can sequence weird plants and animals that you find in unusual places. You can sequence microorganisms that you find in deep sea vents. So that's genomics, right? And there's transcriptomics, which is characterizing RNA species, and there's proteomics, which is characterizing proteins, all the different forms of proteins. And then there's metabolomics. And metabolomics is really. You know that the genome is relatively stable, right? In a cancer cell, it's not as stable. In certain immune cells, it's not as stable. The antibody genes rearrange and so forth and so on. But in metabolism, metabolism is always changing, right? So, for example, in your hepatocytes, right after breakfast, if you're a breakfast person, your hepatocytes are oxidizing fuel, right? But overnight, when your hepatocytes are responsible for keeping your blood glucose up, they are taking things like malate and oxaloacetate and making glucose, right? So they're running reactions in different directions. They're running different kinds of reactions, right? There's a. It's almost like there's a. There's a famous chapter, you know, in. Called Ecclesiastes, and the birds made a song out of it. Back. Back in the day. What is it? A time to. There's a time to sew and a time to mend, a time to burn, time to build up and a time to tear down, right? The. That's the way metabolism is, right? Metabolism has times when it's oxidizing fuel that's catabolic metabolism has times where it's making stuff that's anabolic. And so when it's catabolic, it's taking energy largely that we eat or that we've stored. Right. And it's harvesting these high energy electrons onto NAD coenzymes. And when metabolism is anabolic, making stuff, we're actually taking those high energy electrons and using them to do stuff like make androgens, make estrogen, make cholesterol, make cell membrane.
- [15:30]
B
Wow, there's a lot to unpack there. Because what we usually hear when it comes to cell energy metabolism is ATP, we rarely hear. You know, obviously, if you want to be extremely nuanced and talk to a professor like yourself, you, you've just described a three part path where you've got nmn, nad, ATP.
- [15:54]
A
Nmn. So I knew we'd get to NMN at some point. So there's, there's really four ways. So eukaryotic organisms are what we're talking about. Animals are eukaryotes. Right. Mammals or eukaryotes and bacteria kind of a separate thing. Right. But there are genes and enzymes to convert four different things into NAD and the four NAD coenzymes, nad, nadh, nadp, nadph. So there's something called the de novo pathway that starts with tryptophan. De novo basically means you're making it from scratch. It's like if you were making a cake or you're making. I'm going to make pizza tonight. So I'm doing a de novo synthesis of pizza that's the same as.
- [16:53]
B
Cause I've read a lot about de novo lipogenesis.
- [16:56]
A
De novo lipogenesis. Right. So de novo lipogenesis means that you're starting out with starting materials that look nothing like fats.
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B
Yes.
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A
Like literally it could be sugar. Right. You can take sugar, run glycol. And of course we're very good at this because we're very good at storing taking something like sugar. And there's only so much that we can store as glycogen. Well, glycogen is like polymerized sugar. So that's not really a de novo pathway that's picking up a unit and kind of polymerizing it. Right. That's more of what's called a salvage synthesis, lipogenesis. You're taking sugar and you're breaking it down. Right. And it's broken all the way down to something called pyruvate and then it goes into mitochondria and then there's citrate formation and citrate and I don't know if the details are important to people or not, but the citrate in mitochondria goes into the cytosol and becomes cytosolic acetyl coa, and then that goes to cytosolic acetyl COA and cytosolic malonyl coa. And then you can make fat. Right. So there's a way to take sugar and make fat. Right. And it's a de novo pathway because the intermediates look nothing like the starting materials and the product looks nothing like the starting materials. So that's how our liver and a few other tissues can make NAD from tryptophan. If we got out a whiteboard and I drew the structure of tryptophan and then I drew the structure of nad, you would be hard pressed to find more than two atoms in a row in tryptophan that you find in nad. So that's a de novo pathway, takes eight enzymatic steps. It actually takes a lot of ATP as well to convert tryptophan into nad. And there's many other things that tryptophan is a precursor to. Like tryptophan is used to make protein.
- [19:21]
B
Exactly, yeah.
- [19:21]
A
Tryptophan is used to make serotonin. Yeah, Right. And tryptophan goes through all these so called kind uranin metabolites and some of them go to NAD and some of them go to other things. Okay.
- [19:35]
B
Yeah.
- [19:36]
A
But the other way is what's called salvage and salvage. So just to go back to my pizza tonight, I started last night with flour, yeast, water, salt. Okay. The classical, you know, Napolitano thing. Okay. I guess I, if I really was going to novo, I would have some ripe tomatoes as well. But I do have, you know, a jar of or. Or a can. Can of tomatoes that are, that are going in. But totally de novo means totally from scratch. Okay. Salvage means that you stop off at Trader Joe's and you get a package of dough, or you get a rolled out dough, you get a salvageable unit, you get a usable unit of component, a sizable component of that pizza. It's a difference between making a car from small units versus going to a chop shop. If everybody knows what chop shop is, that's where somebody. There's like a market for like stolen cars or something like that, or wrecked cars. And a chop shop will pull the things out that can be sold again. Right. So salvage would be using those components. Right. And biology is very conservative in the sense that if there's something of value that could be used again and it's going to be used again. Right. So there's something called, there's. So NAD is, is a dinucleotide. ATP is a mononucleotide. It's just one nucleotide. It has one base, it has one sugar, it has phosphates. NAD has two different bases. It has an adenine base, which is the same as an ATP, the base and an ATP. And then it has what's called a nicotinamide base. And then there's a ribose on both sides and there's a phosphate on both sides. So like left to right, depending on left to right, right to left, there's nicotinamide, ribose, phosphate, phosphate, ribose, adenine. That's nicotinamide adenine, dinucleotide. Right. So the most valuable and unique piece of NAD that can be salvaged is called this nicotinamide base, and we call it a vitamin. So it was discovered in 1938 by somebody named Conrad Elvihem. It's kind of a gory story of how he discovered it. But you can, you can buy nicotinamide in the, in the store and your, you know, your body loves it, your cells love it, and it, it goes into cells and there's an enzyme, it's called nampt, and it takes nicotinamide and turns it into NMN inside the cell. NMN is actually nicotinamide riboside with a phosphate on it. NMN doesn't go into cells.
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B
Right.
- [23:10]
A
So it doesn't go into cells because it has a phosphate on it. Right. So but the, you know, the history of science is, is, is weird. And you know about, if it doesn't.
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B
Go into the cell, then what happens?
- [23:27]
A
So basically, like, you could buy nmn. Yeah, it's not fully legal as a supplement in the United States.
- [23:35]
B
Didn't they just recall this a few months ago?
- [23:38]
A
Yeah, there's a, there's an FDA action on it. But, but you can, you can eat it. Right. If you find a safe source of it, what is going to happen is that it's going to be degraded into NR or nicotinamide and then it's going to go into cells. And then whether it's degraded to NR or nicotinamide, it's going to have to become NMN inside of cells and then nad.
- [24:08]
B
So regardless, you're still getting it somewhat of it into the cells, whether degraded or not, which then turns into.
- [24:14]
A
Right. And I've used it in the lab. So like, we've, our expectation was that, and pretty much anybody's expectation would be that NMN and NR would be equivalent when, you know, you do, like, a rat experiment or a cellular experiment, because the NMN has to be converted to NR in order to act. The prediction that other people made, that is false. The prediction was that NMN will just get into cells and then be one step closer to NAD than NR is. Right. Because it already has the phosphate. But Carlos Canto, a number of years ago, knocked out the nicotinamide riboside kinase. Right? So we knocked out the gene that converts NR into nmn. Okay, Right. So if you're an NMN proponent and you're saying NMN gets into cells, it shouldn't matter. It shouldn't matter. If nicotinamide riboside kinase is knocked out because you're delivering nmn, it shouldn't need nicotinamide riboside kinase. It should go straight to nad. Yeah, but it didn't.
- [25:40]
B
So that was the predicted hypothesis.
- [25:42]
A
That was the prediction of the people that said NMN goes straight into cells.
- [25:47]
B
How could they predict that without using a knockout gene? Like, how could you just predict it without.
- [25:53]
A
Well, you can predict. It's a hypothesis. You know, it would be unprecedented because it has a phosphate. So basically, using NAD or NADH or NMN as a vitamin is sort of like using coenzyme A as a vitamin. We use pantothenate, right? So pantothenate is the salvageable piece of coenzyme A, doesn't have a phosphate on it, Right. You start pantothenate, go. Pantothenate is great stuff. It's either vitamin B5 or 6, I can't remember. But pantothenate goes into cells, right? And then enzymes convert it into coenzyme A. Right. It's great stuff. But people don't supplement with coenzyme A because basically it has to be degraded back to pantothenate. And then your cells have to take the pantothenate up and make coenzyme A. So to me, you know, using, you know, NMN as a supplement or intravenous NAD or something like that doesn't really make sense because it has to be degraded to NR anyway. But people are doing it. But, you know, the. Basically the. The biochemistry of it says that NAD and NMN get the phosphates removed, and the biggest piece of NAD that can go into cells is nr.
- [27:35]
B
So explain to me and the audience why this is such a big emerging field. Why is there so much hype around it? You know, we've. I'm now seeing people doing NAD IVs.
- [27:49]
A
Yeah. So there's the.
- [27:51]
B
There's we want more NAD.
- [27:53]
A
So there's the real reason and then there's the hyper reason and they're not exactly the same.
- [27:59]
B
Okay. I would like the real reason because there is a so much, there is so much hype which we're going to get into at the end. But I basically want to know, and I'm sure everyone wants to know, why do we want more nad and why does it become somewhat dysfunctional as we age?
- [28:15]
A
Right. So I think I was starting to say. But I got it from this tangent, right? Are tangents, okay here?
- [28:23]
B
We love tangents.
- [28:24]
A
We like tangents. Okay. We're doing long form podcasting here, but not all day. We're not going eight hours here. We can. No, but I don't think that we will. So I think I said we got really interested in metabolomics because metabolism is what your cells are doing. So we wanted a way to report ohmically, meaning comprehensively, like not sequence 1 gene, that's gene sequencing. But sequencing all the genes is genomics. Right. So we wanted to be able to characterize metabolism ohmically and we wanted to do it quantitatively. Okay. So we developed a technology called quantitative targeted NAD metabolomics. What came out of that, I think is fairly astonishing, which is that what I sometimes term as the crown jewels of metabolism, nad, nadh, nadp, nadph, are not protected like any crown jewels that you've ever heard of. Right. Like where are the crown jewels kept in any European capital? They're kept inside a safe, inside a vault, protected by armed guards, surrounded by a, you know, in a castle, surrounded by a moat or something. Right. So the crown jewels are highly, highly protected. They're not going to be exposed to the elements. Here we are sitting in middle of August 2023. We're actually about to get a very unusual storm. Are you? I don't know if you're going to be around on Sunday or Monday, but we're expecting a hurricane landfall here in Southern California, you know, the first time in 84 years. And so, but in metabolism, in. As we walk around, you know, life, we're exposed to the elements, right. We're exposed to heat, we're exposed to cold, we're exposed to. You just flew in from New York. You have time zone disruption. We are living in oxygen, which we need oxygen in order to run the electron transport chain. But oxygen also gives us reactive oxygen species which have to be detoxified. We love sunlight, but sunlight will damage our DNA. Right. We love food, but overnutrition will challenge our nad. System. A lot of people love alcohol and drugs. Those things challenge the NAD system. In the liver, in the brain, and other places, many different disease processes attack the NAD system. So essentially what our technology allowed us to discover is that many different conditions of metabolic stress disturb the NAD system. So, for example, when we have sun damage to our DNA, something called pyrimidine dimers form. So two T's on the same strand of DNA. It's not uncommon. Like, there's a T every fourth ish nucleotide, and one out of four times it's followed by a T. So roughly one out of 16 dinucleotides is a TT. Solar energy, ultraviolet energy can convert those T's into a cross link. They're supposed to be base pairing with as, but they can get a covalent bond between the two T's and that's bad. That has to be repaired. It turns out that you need NAD to repair that DNA damage. And when your NAD is being. When your NAD is being committed to that DNA repair process and can't do all the other things that NAD is supposed to do.
- [32:45]
B
Right.
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A
Okay. We showed in 2020, during the onset of the COVID 19 pandemic, that coronaviruses through the double stranded RNA genome, which is recognized as foreign, activates five different enzymes that churn NAD. They're called members of the PARP family. And five different members of the PARP family get excited and start churning NAD when in the presence of the double stranded rna. So that's part of the innate immune response. So when our innate immune system gets activated, we basically churn nad. And then in addition, and it's not really known whether it's just intrinsic aging like a timer, or whether it's all of the episodes of metabolic stress that we experience in our lifetime. But there's ample evidence now that NAD declines in aging in a number of tissues. And so that's basically the use case for supplementation with NAD precursors.
- [34:07]
B
Well, evidently, yeah. Because if it is declining and it's essential process for many of these aging diseases, then why wouldn't we want to preserve nad?
- [34:19]
A
So the first indication for supplementing with NAD precursors was basically 100 years ago.
- [34:28]
B
Such as NMN and NR, the precursors.
- [34:32]
A
Well, I still, I mean, NMN becomes a precursor. NMN is used as a precursor. It's not actually a vitamin because it has a phosphate on it. But the three precursors are actually nr, nicotinamide and nicotinic acid, tryptophan being the de novo precursor. And then three vitamins are nr, nicotinamide and nicotinic acid. Nmn, absolutely. Is being used globally as an NAD precursor. Technically, like I said, it's more like somebody taking Coenzyme A to elevate their Coenzyme A. It has to be degraded to something. Maybe that's too inside baseball for this discussion. But what I was going to tell you is that 100 years ago in the American south, there was a very prevalent nutritional disorder called pellagra that affected like a million people. And you don't really see it anymore. You'd have to be a doc, you know, a doctor working with people in very small towns in India or various serious alcoholics to ever see a case of Pellagra. But in the American south, there were. There were basically poor farmers that grew corn and were provided with metal corn milling machines to make the, you know, the ground corn, maize. Right. That they sold back to the people selling them seeds. Right. It's kind of. It's a. It's a very challenging economic model. Right. Where they have to buy seeds and buy, you know, equipment and then sell the, you know, the stuff back. And basically their diet consisted of corn rations, lard, and molasses. Okay. And they had this presentation with diarrhea, dermatitis, and dementia.
- [36:50]
B
Interesting.
- [36:53]
A
And people in Washington, you know, the way the American system works. These are small states. It's not New York, it's not California, but everybody's got two senators, Mississippi, Alabama, Georgia, where this was happening, and it went to Washington. They established the Public Health Service because of pellagra.
- [37:22]
B
Okay.
- [37:22]
A
This is the precursor to the United States nih. They awarded the first Public Health Service grant to study pellagra. That's how important NAD is. It turns out it was awarded to Joseph Goldberger. Everybody told Joseph Goldberger, you're going to go down to the American south and you're going to find an infectious disease that is affecting these folks. He goes down to these places. He goes to hospitals and prisons where there's a lot of people with pellagra. And in the prisons, he sees the prisoners have pellagra and the jailers don't. In the hospitals, he sees the patients have Pellagra. The doctors and the nurses don't. And he said, this is not an infectious disease. And he looks at, you know, the doctors and nurses. I take my coffee black, but a lot of people put milk in their coffee. And the doctors and nurses put milk in their coffee. And they have fresh food. They have eggs, they have meat. And the people with pellagra have corn rations, lard, and molasses, which, by the way, the way you ground, grind, grind corn in Mesoamerica, because corn was indigenous to the Western hemisphere. You grind corn with stone, okay, with alkali stone. And that extraction process will liberate NAD precursors. But if you grind corn meal with these metal corn milling devices that they were sold, there's someone on, on Twitter named Sarah Traber that kind of teaches this, this whole lesson. If you grind corn with this milling device and then you don't have any other fresh food, you're going to be deficient in NAD precursors. So Goldberger actually died without figuring out it was NAD precursors, but he figured out it was a nutritional deficiency and it could be cured with fresh food. And basically all fresh food has NAD precursors, because, like I said at the very, very beginning, NAD is the electron carrier in all of life. So whether you're eating fruits, vegetables, you know, fruits don't have as much cellular stuff as, you know, beef liver. But virtually all fresh foods have some NAD precursors in them. And so you're eating fresh foods, you're getting nad. NAD breaks down to the NAD precursor vitamins, and then you don't get sick.
- [40:12]
B
And then we have energy. It's kind of. You know, what I think about now is genetics versus epigenetics. Because when we look at 20, 25,000 genes, you know, if we look at it from a neurodegenerative standpoint, we know that the. You can switch on these APOE4 genes or you can just not switch them on, and you may get Alzheimer's disease, you may not.
- [40:36]
A
And.
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B
And it's all dependent on environmental factors.
- [40:40]
A
Yeah, environment is huge. Right? You know, we have a gene set that can allow us to live to 120, although we don't know quite how special the people are that are centenarians. But most of us probably don't live to our, our genetic potential because of, you know, environment.
- [41:07]
B
Well, that's what I want to get into now. That was a really brief, brief overview of what I believe that you really do know when it comes to nad. I think if we did have eight hours, we could sit here and talk more on that. But now I want to kind of move the discussion into longevity. And I want to first open up by asking, like, why. Why do we age first and foremost, and why can't we live to 200 years old?
- [41:37]
A
Why we age is a. Is a tough question, but, you know, we do have genetic instructions, right? And all living things have genetic instructions. You know, a bacterium is not going to be a raccoon, and a raccoon, you know, is not going to be a bacterium. Although raccoons will harbor bacteria in their, in their gut, just as we do. And. But, you know, our genes, you know, they specify the sequence of our, of all of our structural proteins and enzymes, and there are what are called morphogenetic, you know, regulators. So animals have something called WINT genes that give us a front and a back and a, you know, a head and a tail and a right and a left and, you know, five fingers on. On each hand and stuff like that. And then based upon the way particular species evolved, they evolved with a particular, you know, life trajectory, let's call it, okay? And it can, it can differ. It can differ widely within closely related species. So a good example is, you know, you're coming from New York City, so you might have a New York City. New York City subway rat in mind. If I say the word rat, which is big, but there's something called a naked mole rat that is basically the size of a house mouse. And we use these mice extensively in molecular biology.
- [43:31]
B
That's pretty much because they're the closest thing to the human.
- [43:36]
A
Not really. I mean, the closest thing to human would be a chimpanzee, okay? And, but they're, you know, they're. It's a size where you can put five of them in a cage. And there's tremendous genetic tools to do, to do mouse. You know, genetics basically is the reason. But, you know, we can actually argue about the strengths and the weaknesses of mouse models of various diseases and conditions. But a mouse and a naked mole rat are basically the same size. They have the same basic body plan, they have the same rough number of genes. And naked mole rat lives ten times as long as a mouse. Ten times as long.
- [44:30]
B
Why?
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A
And it is adapted to a environment in which the species evolved to be able to mate at 25 years old.
- [44:49]
B
Right?
- [44:49]
A
And basically all of its genes, it's not one gene. It's not one magical gene that converted a mouse to a naked mole rat and gave it this 10 times longer lifespan. It's thousands of different genes that give a degree of resilience to the respiratory system, the circulatory system, the skeletal muscle system, the brain, the, the hearing system, the odorant detection system, all of the systems of the naked mole rat that allow it to live and reproduce and take care of itself for 25, 30 years. And by the way, humans are kind of more similar to the naked mole rat than the mouse in the sense that humans are extraordinary good agers. So there's a book I reviewed, I reviewed a couple of books on. On longevity. And the one that I really liked was by Stephen Ousted. It's called Methuselah Zoo, Methuselah's Zoo. And the idea of Ousted's book is, let's study animals that are really good agers. And earlier in his career, he drew a line, okay, where it's the animals weight in kilograms along one axis and their lifespan in the other axis, I think the Y axis. And generally most animals, the age, the longevity kind of scales with size, right? So you have huge whales that have very, very long lifespans, right? And you have little mice and beetles and flies that have really short lifespans. And you put hundreds of different species on this thing. It approximates a line, right? And then what Ousted and his trainees realized is if an animal is above the line, that is, it has a longer lifespan than you would expect from its size, it must have something. It must have figured something out about aging, right? So the naked mole rat is above that line. Humans are above that line, right? Okay, so our closest, you know, relatives are chimpanzees and, like great apes, right? Gorillas. So gorillas are bigger than us. Chimpanzees are a bit smaller than us, but we live longer than both, right? Gorillas don't outlive us, even though they're bigger and heavier. And. And we live, you know, quite a bit longer than. Than chimps. And if you look throughout the animal kingdom, generally speaking, with. With some very interesting exceptions, generally speaking, animals live as long as they're reproductively capable because basically that's what is selected in evolution, right? Is that, you know, the reason someone said something ridiculous the other day, you know, on Twitter, someone said something ridiculous on Twitter and said that humans were only designed, which is a weird word to use, to live 30 years and, you know, 100,000 years ago, you know, you know, the grandparents would be like, stealing food from their grandchildren. No, no. If there was a species that stole food from its babies or grandchildren, that species would not exist.
- [49:09]
B
Yeah, there's a grandma hypoth. Is it grandma?
- [49:11]
A
Yeah, yeah, let me get there just one second. But. But that is literally the exact opposite.
- [49:16]
B
Was this person in science.
- [49:21]
A
You can look it up.
- [49:21]
B
Okay.
- [49:24]
A
But strangely enough, the person gives very expensive seminars on longevity. People pay money for the person's content, which is weird, but the species did not succeed by stealing from our babies. Species succeeded by either fecundity, which means having lots of babies and And. Or caretaking, meaning we have lesser number of babies, humans being the extreme, extreme example. Right. Where there's a tremendous amount of caretaking of the offspring. And then bam, you hit the nail on the head that the most interesting exception to the rule of an animal that outlives her reproductive capability is the human female.
- [50:27]
B
Human.
- [50:28]
A
The human female, Right. Average onset of menopause, 51. Most babies born by the time she's 35 or 40. Right. Much higher fertility in her 20s than even in her 30s and 40s. No judgments here, but I can show you the data.
- [50:52]
B
But can still conceive in there.
- [50:53]
A
But can conceive. But absolutely can conceive. I mean, onset of menopause and not till 51, but life expectancy into the 80s. So three decades plus. Right. Of good health, better life expectancy than men at almost every decade of our maturation. Better health in her 50s, 60s and 70s and 80s than men. Yet onset of menopause is at 51. So I just told you that in general, the selection in animal lifespan, the selection is there's a lot of selective pressure for us to be born. I mean, every animal, okay, beetles, flies, birds, lizards, we have to be born, we have to avoid predation, right? And then we have to be able to get to the point where we can get our own food. Then we have to get to sexual maturity, and we have to be able to identify mates. And so that requires a sense of smell, of mobility, vision, all kinds of things, animal sex appeal, whatever that is, and then be able to reproduce. And then you either reproduce with lots and lots of babies or good caretaking of the babies so that your gene set is passed on. And that's why we have the animals that we have. Yeah, right. So we don't have animals that stole from their babies or their grandkids. That's literally not the way evolution works. We have animals that have lots of babies and. Or provide for. For their babies and grand grandchildren. And the grandmother effect, right, Is that we think that in human evolution, because humans do live longer than chimpanzees, right. Is that. But the, you know, if there were a system that preserved, you know, primary follicles, right. And fertilizable eggs that you could have into your 50s and 60s and 70s, you know, it appears to me like it would have resulted in many more birth defects. Right. And many more kind of less viable offspring. Right? So in the course of human evolution, the reproductive period for females was kind of condensed from 15 to something in the 40s. Right. 40s to 50. But then women are still very capable because they have played such an important role in child rearing and even provide advantages to grandchildren. So that's the grandmother hypothesis, that women's reproductive period was, was condensed into a period that is substantially before the end of her, you know, lifespan. But in men, fertility just declines slowly. I used, I used the term peter out once and people cracked up. But it's true. Basically there's a sperm count that just declines and there's probably a sex appeal that just decline. So there's not very many men that, you know, father kids when they're 70 or something. But it's possible.
- [54:54]
B
It's very possible, I think. Isn't. Can't men conceive to their 90s?
- [55:00]
A
Yeah, if they live to their 90s. Right. And that's basically the way most animals are. So the, you know, the, the Greenland shark that lives to 180 or 190 is reproducing when it's 180. It's an apex predator. Right. There's not any thing that it has to really worry about other than like boats or people. And it's got sex appeal when it's 180, which is why every aspect of its body works really well when it's 180. It's not one longevity gene. It's the difference between a Greenland shark and other types of sharks that live much shorter is hundreds or thousands of genes that allow all of its systems to work really, really well for all of that time. Because reproduction involves everything, right? Reproduction involves musculature, brains, being able to smell, vision, you know, everything, right? So that's, I think that's the way, you know, evolution works. And that's, that's why animals have the longevity that they have.
- [56:14]
B
So then, okay, so why don't we talk about sirtuins? And since we're on this topic of longevity, I know that I've actually had David Sinclair on the podcast. This was a couple of years ago, actually, during the pandemic. But we, we spoke about sirtuins and I have understood his theory of aging and longevity. And I'd love to know what your, your.
- [56:37]
A
Yeah, well, there's a group of people that have falsely claimed that sirtuin genes are conserved longevity genes. They're not.
- [56:48]
B
And actually, I do want, for everybody, I do wanna read your, the title of your wonderful paper that was released, I think 2022, October or September 2020. Sirtuins are not conserved longevity genes. I had to tear apart. This study highlighted about six or seven Times. So you're basically saying that sirtuins are not long.
- [57:11]
A
No, no, no, no, no, no, no, no, no. So the. The original result was from the 1990s in the lab where David Sinclair was a postdoc Lenny Guarenti's lab. There were a number of very excellent people that trained there, and they were using yeast. Remember I told you that I did my graduate work on a yeast enzyme. I got nothing against yeast. I did yeast when I was in industry. I did yeast for the large part of my initial independent academic career. Yeast has taught us important things about the cell cycle. It's taught us important things about cancer, believe it or not. It taught us things about pro hormone processing. And the Grenty lab thought that it might tell us something about aging. I think yeast aging only tells us about yeast aging, unfortunately.
- [58:17]
B
Yeah.
- [58:19]
A
And there are two different models of yeast aging. There's one model where you look to see how long cells live. Right. So we can go back to my example of making pizza. So the yeast in the jar are dried yeast. I don't know the last time that they were dividing. Right. I don't know when they were put in the jar. I bet they were put in the jar a year or two ago. Right. And, you know, I gave it, you know, water and flour and a little bit of olive oil. And that's fuel. And, you know, it. It got bubbling right away. Right. And so if yeast had a short lifespan, that's called a chronological lifespan. We wouldn't. We wouldn't have yeast. Right. We've literally been carrying around yeast in our, you know, clay pots for thousands of years. Okay, Right. So if you look at agriculture, development of bread making, winemaking, beer making, we're going back to Mesopotamia, you know, and other places in the world. And that's when. That's how long we've been cultivating yeast. So. So that's. That. That's. That's aging. Right. So you can see how long yeast will survive when you basically dry it down and you. You let it sit for. For a while. And then there's another assay of aging that was done by the guarantee lab. It involves taking individual cells and putting them on a petri dish. No one would do. You wouldn't ever do this for making pizza. Right. But you could put individual cells on a petri dish, and then you can kind of like install a graduate student or a postdoc in front of the petri dish and microscope. And then every 90 minutes, the yeast cells divide and what's called a mother cell will produce a daughter cell. The yeast divide by what's called budding. It buds into a daughter cell. And if you remove that daughter cell, you can see how many times they're capable of producing a daughter cell. That one cell that you arrayed, you might have 50 individual cells on a petri dish. And you can determine how many times the mother cell produces a daughter. And the answer is around 21 times. And if you calorie, restrict it, if you have lower glucose, lower sugar on the plate, it will go longer, it will divide more than 21 times. But if you go back to the yeast culture, you'll never find a yeast cell that is divided 20 or 21 times. That's literally one out of five million cells is that old in the culture. 50% of the cells in a culture are brand new cells, right? They just buded off. So 50% of cells have never been what's called a mother cell. 25% of them have been a mother cell one time, 12 and a half percent have been a mother two times. It's an exponential series, right. And 1. And so the effect of sir2, the original sir2 in gene was called yeast sir2. The effect of this sir2 gene was to allow in this one particular assay of aging, it was to allow those 50 arrayed mother cells to divide not 21 times, but 25 times. But this is an effect of an incredibly rare cell. 1 out of 5 million cells is providing an advantage of 1 out of 5 million cells. And I want to go back to the jar of yeast, right? If you do the assay with, and that represents basically the whole culture, right? You grow yeast and you look at their ability to, to be revived. It turns out if you delete, if you delete the SIR2 gene, that culture lives longer chronologically, it's literally the opposite, it's literally the opposite of an anti aging gene in one yeast aging assay. And then it advantages, provides an advantage for 1 out of 5 million cells in the, in the assay that they, they used.
- [63:42]
B
So then what was David trying to achieve with this SIRT2 gene?
- [63:48]
A
Well, basically they had this idea that because they found advantage, actually Matt Kaeberline, I did, did some of the podcast, Matt did some of the very, very, very, very first experiments with Sirtu in yeast. And then David in 1997 showed that it had to do with what's called ribosomal DNA circles, right? And ribosomal DNA circle. We don't have ribosomal DNA circles in humans and worms don't have them. And Flies don't have them. And so they had a very peculiar idea that because they found it would have been great if it were true, that the gene that they found in their particular assay of yeast aging, they proposed that this is going to be an anti aging gene in worms and flies and mice and people. Here's the tragic part. There were irreproducible positive results published in the early 2000s. So the guarantee Lab published that extra copies of the worm sir two homologous gene extend lifespan in worms. And then David Sinclair in collaboration with a fly group claimed that extra copies of the fly Drosophila sirtu gene extended lifespan in flies. Which to me that would be mind blowing. Right. Because yeast is a fungi. Yeast evolved its whole lifestyle before there was any animal on this planet. So the idea from this Guarantee Sinclair set of experiments is that somehow, whoops, I just almost caused a little accident here, got so excited. But the mind blowing concept is that fungi have a gene like yeast has a gene that anticipates the causes of death and the causes of aging in animals. And that you have extra copies of that same one gene in animals that's going to extend lifespan. And then they got results that seem to be in support of that but.
- [66:25]
B
Couldn'T produce the results.
- [66:27]
A
They continue to claim that those results are true. Other people cannot reproduce those results. That's a bad sign. If you're finding something that is authentically true, other people have got to be able to reproduce it. It's like this Fakhakta thing about the semiconductor about two, three weeks ago. Right. People are trying to reproduce it because if it's really true that there's room, room temperature, superconducting, it's going to enable all kinds of, you know, high speed trains and all kinds of things that, that we don't have right now. Right. But no, it turned out to be conventional, you know, magnetism. And so, you know, so it's really a problem.
- [67:14]
B
Yeah.
- [67:14]
A
And you know, and they, and further, you know, David, you know, claimed to discover resveratrol as a Cert 1 activator. And, and it's not, you know, resveratrol, you know, it's a, it's what's called a biochemical artifact. So there's a synthetic peptide that they used to do that assay. Resveratrol interacts with the synthetic fluorescent piece of that peptide. It does not interact with, with Cert 1. The company that they established.
- [67:52]
B
Has he retracted that now? Oh, okay.
- [67:54]
A
He hasn't still today, in 2023 he's got a business that sells resveratrol to the general public. And that's ludicrous and you know, and claims that it's activating SIRT1 and that SIRT1 is a longevity gene. And there's two false statements there. It doesn't activate SIRT1 and SIRT1 is not a longevity gene. So it's astonishing to me.
- [68:23]
B
How is that? Okay, that's interesting that it's such a big public name is out there doing that. If you can conclusively say that SIRT1 is not a longevity gene.
- [68:35]
A
SIRT1 is not a longevity gene in worms, it's not in flies, it's not in mice, and it's not in people.
- [68:44]
B
Are any of the Sirtuins Sirt6?
- [68:48]
A
You know, I mean, all of their seven Sirtuin genes, they're all, you know, interesting.
- [68:53]
B
What does it stand for?
- [68:55]
A
It stands for silent information regulator. So the original yeast gene was found by somebody named Jasper Rhine. He's a yeast geneticist. Rhine and Herskowitz. It's from, I think it's literally from Jasper Ryan's 1975 PhD thesis where he's looking at yeast mating type. Believe it or not, there's two mating types in yeast. It's not male and female. It's something called A and alpha. And, and there's a way that yeast don't express both mating types. There's a way that yeast are not bisexual, you know, basically. And it involves the SIR2 gene, you know, repressing the opposite mating type information. And then the kind of SIR two thing was kind of like rediscovered with the so called anti aging phenotypes in the 90s in the guarantee Lab by Matt Kaeberline, David Sinclair and others. But the problem is, like I said, is that it's only one of the two aging assays in yeast. It only advantages 1 out of 5 million cells. It has the opposite effect in chronological aging in yeast, which was done by Valter Longo, who's a very prestigious aging researcher here in Los Angeles. And then it doesn't translate into animals.
- [70:30]
B
So that SIRT6 gene, is there an activator for that?
- [70:34]
A
So SIRT6 in. Some people looked at SIRT6 because they thought that sirtuins were longevity genes. So it's sort of like looking for your keys under the street lamp, right? If you lost your keys somewhere in a 1 mile radius and there happens to be one street lamp in the 1 mile radius and you might only look under the street lamp because that's A place where you could, your cues would be illuminated if they were there. But the, the problem with looking at SIRT 6 or SIRT 2 or SIRT 3 or 5 or something is that there was a presumption that these are gonna be longevity genes. Right? That's a falsely premised assumption. But when people looked at SIRT 6, they found that in certain mouse strain backgrounds, you get a bit longer lifespan. To me, it looks like it's not going to translate into humans because SIRT 6 is a positive regulator of gluconeogenesis. Right? This is this overnight process where our liver elevates our blood sugar. The problem is humans, as we age, we tend to have a worse metabolism and our blood sugar rises, which is why so many people take things like metformin. Right. To lower their blood sugar. Again, I don't think that metformin is necessarily going to be a successful longevity drug, but there are trials of metformin as a longevity drug. SIRT 6 overexpression elevates blood glucose. That's good for a mouse, bad for a human. Bad for a human. Mouse has too low blood glucose as it gets to 2 years old. Most, a lot of humans have too high blood glucose as we get to 70 or 80 years old. So Sirt 6, you know, is an interesting mouse, but I don't know that an activator of SIRT 6 is going to be that valuable to us.
- [72:53]
B
Okay. What I would love to understand is how can we, in your words and everything that you've learned, how can we slow the aging process?
- [73:03]
A
I think that we can, we definitely can age better, right? You can age better and you can age worse. And I think largely it's following mom's advice, to be honest. Right. It's a good diet, it's high physical and mental activity, social engagement, sleep, don't smoke, don't do drugs, don't drink alcohol in excess, take medications that you need to take, don't take drugs that you don't need to take.
- [73:45]
B
Drink clean water.
- [73:46]
A
Clean, clean water. Right. And so that's almost all of it. Right. I think that there's a use case for nr, excuse me, as a molecule that promotes resiliency and repair. I think that in coming years, I think that currently we have human evidence that NR is anti inflammatory and in combination with other molecules that it accelerates time to recovery of COVID There's a lot of long Covid studies that are being done. There's potential for wound healing and fatty liver studies in which we may get some positive results. There's a lot of anecdotal data that people have better workout recovery and recovery from minor cuts and scrapes and that potentially you age better and you can kind of maintain your muscle mass with, with good, good exercise and are. But I don't necessarily believe in magic pills. You know, I. There. If there were single longevity genes, dominantly acting longevity genes, then CRISPR would change a lot. Right. Because if there were a dominantly acting longevity gene, then we would want to like modify our genome to have more of it. Right. Or we would have, we would want an activator of that gene. That was kind of the resveratrol idea. Right. But you know, SIRT1 isn't a dominant active longevity gene. And the most powerful single genesis that affect longevity in animals are actually recessive alleles of growth promoting pathways. You know about that, the dwarf mice business, right?
- [75:57]
B
Yeah.
- [75:57]
A
So like there are dwarf mice, they have basically mutations in pituitary pathways. And then these are tiny little cold mice that can't compete for food and are infertile, that live twice as long as other mice. So. And you know, no one wants to. I don't think there's a lot of humans that would want the difficulty of being a dwarf mouse. Right. Because those are not happy little campers. And in fact, if you go to the things that are called longevity clinics, so here we are in West Hollywood. You could go into, you know, clinics in order to look really good for your next movie shoot or something like.
- [76:58]
B
That, they would hook you up to an IV an nad.
- [77:02]
A
Well, they would give you, they would potentially give you growth hormone and anabolic steroids. And basically these mice don't have growth hormone and they live longer. And we know that pro athletes that have taken growth hormone and anabolic steroids become relatively fragile much more rapidly. And so it's probably, it's not clear yet that you can directly target the aging system, which is kind of a goal of geroscience. It would be wonderful if we could, we can target the NAD system and potentially enhance people's resiliency and repair. But I don't think that we're necessarily going to extend lifespan that way. I think that our gene set is limiting our lifespan. We potentially are going to enhance our health span and a resiliency and repair. But that's something that has to be demonstrated in placebo controlled trials.
- [78:13]
B
Okay, so mainly what I want to know now is there is just so much happening on social media, which I'm sure this is the reason why you're probably not on Instagram. And for your sake, it might hurt you if you go on there and see the abundance of information out there, albeit most likely not true, around longevity. This helps you live longer. This helps you live longer. Even back to the resveratrol saga, you know, I, I do believe David was out there also suggesting a glass of wine to increase resveratrol levels to help with longevity, which I think is also scary. What currently is false. What are we reading that is false around longevity?
- [79:03]
A
You know, none of the. The thing is, I don't even know where to start.
- [79:16]
B
Okay, give me the top two.
- [79:19]
A
The, you know, the. There's a lot. There's a lot of fads, right? There's a lot of fads in diet, you know, like fasting, like intermittent fasting. Right. And then there's extreme practices of all sorts, and there's people that are highly prescriptive about all sorts of, you know, physical activities. So basically, first of all, you have to live your life. Yeah, right. And you have to figure out what, what works for you. There are people that are, you know, claiming that we should all be doing intermittent fasting or some type of calorie restriction. So, I mean, calorie restriction is a way to lose weight and, you know, effectively. And so you have to be in a caloric deficit in order to lose weight. One of the ways that your body is going to respond to that is by lowering your energy expenditure. Okay. I'm personally at pretty much the weight that, that I want to be. And, and so, you know, caloric restriction doesn't really make any sense to me in terms of intermittent fasting. I'm on team breakfast. And, you know, I am very productive when I get up in the morning, have my coffee and, you know, have breakfast and I can get to work and I can have a very good workout and I can have good mental, you know, capacity. And so there are people that are just highly, highly prescriptive about the way you need to live your life that I just don't find particularly helpful. On the other hand, overweight is a huge problem. Right. And you know, I work in a, in a cancer center, and if you look at the global statistics, there's essentially only one organ site that is becoming more prevalent in cancer and more lethal in cancer, and that's liver cancer. And, and that's because the lesion that predates most hepatocellular cancer is fatty liver. And there's something like a billion people on the planet right now that have fatty liver. And the percent of the people with Fatty liver now that become type 2 diabetic or develop liver cancer could further degrade human life expectancy and, and you know, really challenge global economies because it takes, you know, so, so much, you know, medical care to take take care of people with, with type 2 diabetes and hepatocellular cancer and it's incredibly lethal. HCC is incredibly lethal. So for the first time ever, there's actually drugs that actually make calorie restriction possible for sustainable for most people. Right. So these GLP1 receptor agonists like semaglutide and so forth. So that's exciting, right? But that's indicated for someone that is living with overweight that you know, that wants to, to, to be able to restrict their, their appetite. So okay, calorie restriction, you know, caloric restriction makes sense. But you know, caloric restriction extends lifespan of caged mice. It extends lifespan and health span of primates as well. But a lot of the comparator groups are actually overfed. Right. So caloric restriction, the question is always compare to what? Right. So you know, I think that most people, you know, can probably would probably do better by eating more plant matter and you know, and drinking less sugar sweetened beverages. But I'm not going to go around and advocate caloric restriction on the Internet because some of the people that are most likely to take that advice are already really lean and they're basically the worried. Well, right, and somebody that is living with overweight pretty much knows that they need to move more and eat less, but may not be able to do that. Right. So I just, I don't see the point in being an advocate for caloric restriction. There's a lot of people that are sensitized to advice on the Internet. I call it kind of podcast disease. You know, the present company excluded, but there are people that listen to podcasts to try to get every little bit of advice that they could use to so called optimize their life. Somebody that tells them when they should have their coffee in the morning. I don't understand why we need to give that kind of advice, why we.
- [84:48]
B
Need to wait 90 minutes waking up to have our coffee.
- [84:53]
A
We 5 million people or 7 or 8 billion people on the planet have different needs in the morning. Some people have childcare, some people have to get to work in 30 minutes and don't have 90 minutes to go and, and take a walk and wait until the sun is at 15 degrees above the horizon. Some people live in the, you know, near the north and south pole and near the equator where that 15 degrees above, you know, the horizon is, you know, a different time of day. And, you know, you can't, you can't make, you can make advice for people, but it doesn't make sense for vast numbers of people to follow it. And so, you know, I just think there's too many people that are too prescriptive about stuff and that people have to live their life and come up with a sustainable practice like exercise, for example. So, you know, the people that I like to follow that talk about exercise and fitness are all about sustainability of.
- [86:07]
B
The activity, of course, because adherence, we know that adherence is the best form of consistency, which equals, you know, so.
- [86:15]
A
So there's, there's some people that are saying, okay, well, should I do like 3 reps to exhaustion or, you know, or should I do multiple sets of 10 or something like that? Well, if you're at that level of refinement, you're good.
- [86:31]
B
Just pick up the dumbbell.
- [86:32]
A
You're, you're, you're good. And, and then, you know, and you know, because it turn. It turns out that walking is great. Running, swimming, you know, mountain climbing, bicycling. I don't have a standing desk because it wouldn't really work for me, but treadmill desk, you know, that kind of thing. A lot of those things are gimmicks. If it works for someone, that's great. But, you know, chasing around kids, that counts. You know, walking your dog, that counts. Being around people of a variety of ages, taking care of other people, that's a physical activity. So, you know, there are people that will point out that if it feels like, you know, play and if it's meaningful to you and, you know, and you do it, then that's the right activity. So, you know, I think that people have to, have to find their thing that they can stick with and then do it. But, you know, support groups, coaching, whatever it takes.
- [87:49]
B
I want to finish up by. I think I've asked you this question six or seven times already in the episode, but I do want to get to the bottom of these IVs and how to actually increase levels of NAD. I mentioned offline that there are companies who now are selling NAD powder as a supplement, you know.
- [88:11]
A
Right. You know, well, it's, it's the same problem as nmn, Right. So it basically has to degrade to nr. Right. And, you know, safety is, is, is really paramount here. Right. So, you know, you talked about, you know, your food and water being not contaminated. Right. And so, you know, if you, if you buy, you know, supplements, you don't necessarily know what's in them unless they've gone through a rigorous, you know, program of testing. So we did that with nr, you know, so I, you know, I discovered the vitamin pathway and then a number of years later it was, you know, the IP was, was licensed and commercialized and, and we, we did the human testing. Right.
- [88:56]
B
Is that true? Niagen?
- [88:57]
A
Yeah, yeah, yeah. So Niagen is like the branded, you know, patented nr and we know that's safe for humans and it's going to deliver the same thing that NAD or NMN do, which is going to deliver NR to cells. Now one thing that I didn't say is I didn't say why. So I said that tryptophan to NAD is an inefficient process because tryptophan is used for other things, requires a lot of ATP and it doesn't work in all tissues. Right. And neither does nicotinic acid niacin. Niacin also gives you a high flush reaction if you take high dose niacin. The nicotinamide pathway and the NR pathway are active in all tissues. But the interesting thing about NR is that in many of these conditions of metabolic stress that I discussed, like the coronavirus infection and in neurodegeneration and in heart failure, and we think in aging as well, the NR pathway is upregulated. So it's like your cells and tissues are looking for NR when the NAD is being depleted. So we think that that's the added value of nr, that it costs less ATP for cells to make NAD coenzymes from the NR pathway because it already has the ribose on it. And, and so that's kind of the use case of nr. So we think that you can age better with, with NR and it will, you know, promote resiliency in terms of iv, you know, I don't really know where they're getting the iv. I don't know how clean that whole, you know, system is, but all it's going to do is going to deliver nr. I've heard it's relatively painful as well.
- [91:01]
B
Very painful.
- [91:01]
A
And so I think what it an inflammatory reaction because normally NAD is an intracellular metabolite. So cells have an innate immune response, just like they have an innate immune response to double stranded RNA because it's, you know, it's interpreted as a viral product. Cells get kind of excited when they see things like extracellular ATP, nad, intact mitochondria, cell free DNA and so that produces an inflammatory reaction. So I think it may be painful because it's producing this inflammatory reaction. So I don't really see a use case for intravenous nad. You can basically get the effect from oral nr.
- [91:56]
B
Wow. No matter how many podcasts I do, which I think I'm around 300, the answers really are sleep, eat well, social connection, sunlight and exercise. It's, you know, at the end of the day, I feel like we're spending billions of hours, billions of money to try and find the answer to this evolutionary process that is just, it's just so nuanced and just, I feel like the answers are just eat.
- [92:33]
A
So mom, would, mom, would mom say what my grandparents? Exactly. Yeah, right. I don't really see a tremendous amount of human longevity tech right now. Like I don't see the consumer use case for age tests. They don't agree with each other. They don't measure what they report to be measuring. They're sensitive to inflammation. So they'll say that you gained 10 years during a COVID infection and then you lost 10 years when you resolved the infection. Okay, so let's admit you're measuring infection, you're measuring inflammation. And then there are people that are trying to turn every single bio measurement, every single biomarker into an age. There's a person out there that says his Testosterone age is 18 even though he's in his 40s. But guess what? Yet you're juicing with testosterone. So you're not 18, you're juicing with testosterone. So they're making a mockery of these biomarkers because the whole thing can be gamed. Right? You sell somebody a kit to measure their age and then you give them these various supplements and drugs that are basically goosing the, the age test people. So I'm basically a very, very healthy 61. Okay, but I'm 61.
- [94:06]
B
Yeah.
- [94:06]
A
And I'm going to be 62 in a couple of months and, but you know, I chase around a couple of kids. I have a wife that is a marathoner and you know, I have a lab full of young people and you know, I have people that depend on me. So I'm, I'm active and I'm, you know, but I don't, I don't see a use case for taking an age test that gives me some number for me to brag about it's function. Right? It's, can you still do a pull up? You know, can you, you know, do you have a sex life? Can you play chess with somebody, you know, half decent? Can you ski? That's what matters. And so to Me, the age tests is kind of a racket. It's also a research tool. Okay, the age tests are a research tool, but there's not a consumer use case for them.
- [95:08]
B
I think Brian Johnson would disagree.
- [95:11]
A
Well, he's literally selling, you know, a, a plan. Yeah, but, but it, it makes no sense because, I mean, the, the things that he's doing that are making him more fit in his 40s than he.
- [95:28]
B
Was saying that he's at the biological age of 18. I think it is.
- [95:31]
A
Well, no, but, but, but, but it's tests that are totally biased by the supplements and drugs that he's taking. So, like, he literally tells you his testosterone age, and then if you look in his protocol, it's testosterone. So, you know, it's not meaningful. The things that he's doing of, you know, eating lots of veggies and, and working out and prioritizing sleep are. That's his functional fitness. Right. And then, you know, then you can add hair dye and laser, you know, treatments to things which is superficial and other things that are just, you know, not going to work out for him that well in the long run because, you know, testosterone replacement therapy will, if you're a guy, literally shrink your balls and lower your body's endogenous production of androgens and potentially accelerate aging. So, you know, he, he's measuring himself to try to have a higher level of testosterone and a higher level of growth hormone. And I told you, the one thing that we learned from one of the most powerful things that we learned from mouse, you know, aging studies is that the growth hormone deficient mice live longer. So if people that are juicing with growth hormone and testosterone are going to, you know, feel they're going to be able to put on muscle mass maybe like they did in their 20s and 30s, but are probably going to be aging more rapidly. So it's not evidence based what he's doing.
- [97:24]
B
He may be coming on the podcast, so that's going to be interesting. Charles, this episode is probably one of our longest and most in depth. I think people need a pen and paper for this one. Are you only on Twitter? I want to point people to your work.
- [97:39]
A
I'm on Twitter. I mean, I'm on, you know, I'm on Instagram and Threads and most of that other stuff, but I'm not, yeah, I'm not really active on it. And so the only place that I've really got a substantive following, I think, is on, is on Twitter.
- [97:59]
B
Yeah, we're going to point everyone to there. And I'm very excited to follow your work. I think that we all have another podcast next year just to catch up.
- [98:06]
A
On all of this. Good, good, good. People can really, if they want to really follow my work. There's a website, it's brennerlab.net and, you know, that's where our publications are. But I try to let people know if I'm giving a talk that's open to the public. I try to let people know on Twitter and people can ask me questions there.
- [98:31]
B
Thank you so much.
- [98:32]
A
All right, thanks. It was a pleasure.