Speaker: [00:00:00] Different plants work differently for different people, different proteins, different fats, but at the end of the [00:00:05] day, adequate NAD levels mean your mitochondria can handle with your
Speaker 2: diet. If you could [00:00:10] activate the sirtuins without the calorie restriction, that would be the best thing. And I think that's [00:00:15] what you would do by boosting NAD.
Speaker 3: Leonard Guarente is a world renowned scientist and [00:00:20] pioneer in the biology of aging, whose groundbreaking discoveries on sirtuins and longevity [00:00:25] pathways have reshaped how we understand healthspan and the future of human life. He's not [00:00:30] just studying aging, he's redefining it. If NAD
Speaker 2: levels [00:00:35] decline, if they don't stay high enough Sirtuin activity will fall, and you will lose [00:00:40] this repressor
Speaker: of aging.
We must keep our NAD levels at youthful [00:00:45] levels in order to be healthy over time. When's the right time to [00:00:50] start enhancing NAD? You're listening to The Human Upgrade with Dave
Speaker 4: [00:00:55] Asprey.
Speaker: When I first [00:01:00] learned about biological clocks and that we could measure [00:01:05] aspects of aging to see whether we're doing a good job or not, I was so excited because before [00:01:10] that it was, well, did the mouse die or not?
Let's hope that I'm a mouse kind of a thing. What's your take on [00:01:15] how good biological clocks are now?
Speaker 2: I'm a fan. I'm a pretty big fan. [00:01:20] It's, it's in the context of what are called biomarkers of aging. So those of us who have studied [00:01:25] aging in the lab use model systems. Okay. So over the years, we've [00:01:30] studied aging in yeast and in the roundworm and in [00:01:35] mice.
And in those three systems, you can use as the [00:01:40] readout for aging, how long does an animal live? Longevity. Okay. [00:01:45] Lifespan and for yeast, you know, that will be an experiment that takes weeks [00:01:50] for worms. It might take a month. And for mice, it would take two to three [00:01:55] years, but still doable. In humans, that kind of study is [00:02:00] extremely difficult to impossible.
Speaker 5: Mm
Speaker 2: hmm. So you really need something else. You [00:02:05] need a biomarker that is really reliable, that is a [00:02:10] readout of biological age. So chronological age is easy. That's how old you are. [00:02:15] Uh, but biological age is, is tougher. So biological age is [00:02:20] sort of reflected in Your appearance, people look younger than their [00:02:25] chronological age or older your activity, people who are biologically younger or [00:02:30] more active and so on and so forth.
So, what one [00:02:35] needed is, uh, and scientists like sort of quantitative measures. Okay, so [00:02:40] you do this particular measurement and you've learned biological age. And there really [00:02:45] hasn't been anything until about 10 years ago or so when [00:02:50] these biological clocks came out that are based on something called DNA methylation, [00:02:55] which is wasn't really strongly studied in the aging field [00:03:00] before that.
And I was extremely skeptical when it was first [00:03:05] claimed but what they showed is that, and it was all done by basically machine [00:03:10] learning and AI. It was done by having a lot of data and having biological samples [00:03:15] of people of all different ages and measuring DNA [00:03:20] methylation. And in our genome, we have maybe 1 to 10 [00:03:25] million sites methylated.
Okay, that's a lot. And they use, [00:03:30] so you really can't, Analyze it by eye and decide what methyls [00:03:35] would tell you something about aging. Let's say it's, uh, you know, a tiny fraction of the [00:03:40] million, you know, let's say it's a thousand or a hundred. Never see that. You can't see it. [00:03:45] So they let the computer find them.
And they then [00:03:50] from, and that's called the, the, the data set that provided the algorithm. And the [00:03:55] algorithm is you look at the quantity, quantify how much methylation is in these [00:04:00] particular. G residues sprinkled across the genome. Okay, so then you have to go to an [00:04:05] experimental set now, a new, totally new set of data, and use that [00:04:10] algorithm and predict what the biological age is, [00:04:15] of this, that, or the other thing.
And biological age and chronological age, of course, are [00:04:20] correlated. So most of the early studies were done with chronological age, which is, [00:04:25] Easy, right? And they could do it. They could predict [00:04:30] chronological age based on measuring methylation, initially at a [00:04:35] small number of sites, a few hundred. So from that, it [00:04:40] evolved, and I started to believe it at that point into, um, using that [00:04:45] data in studies that had been done for a long period of time.
That was one of them is called, I [00:04:50] think, in Chianti.
Speaker 5: Mm hmm.
Speaker 2: And to use data that was taken from [00:04:55] people at a certain age, let's say 60, and the [00:05:00] study followed these people for, let's say, 30 years, so by then you knew what the [00:05:05] mortality looked like in this population, and then apply the algorithm to those [00:05:10] 60 year old blood samples and predict how long they would live, and now you have the actual [00:05:15] data, actuarial data, how long they lived, and you could do it.
You [00:05:20] can make accurate predictions. So that's when I really started believing it. Now, the [00:05:25] most recent breakthroughs. So that's kind of the phase one, phase two [00:05:30] clocks use that algorithm, but they incorporate. Other [00:05:35] measurements to get an idea of physiology. Okay, so your [00:05:40] health, if you go for a good physical, they'll measure a lot of things analytes in your [00:05:45] blood.
Okay, glucose. Right. It's a good example, but others as well. [00:05:50] Fats, cholesterol, and so on. And that will also affect the [00:05:55] doctor's outlook on your health.
Speaker 5: Mm hmm. Mm hmm.
Speaker 2: So these were [00:06:00] incorporated into an algorithm. So for a person, if you had that kind of blood [00:06:05] data, plus the methylation data, and you put it together and, uh, get a [00:06:10] composite prediction you were getting closer to the biological age of that person because [00:06:15] all the, the measurements, blood measurements and so on, would give you some idea of how healthy that [00:06:20] person is.
That would go in in addition to the the methylation test. [00:06:25] And so we got closer and closer to being able to measure biological age. [00:06:30] So these days, the tests that are out there, including the test that Elysium the company I, [00:06:35] uh, helped get going has, um, and and the [00:06:40] test will measure methylation.
Okay, but it has all these inputs into the [00:06:45] algorithm, and so it will give an output of your biological age and pretty [00:06:50] accurately,
Speaker: I've seen a few people say, Look, you can't extend human life. There's [00:06:55] no evidence. Biological clocks are not scientific. All you can do is [00:07:00] have a good health span. What do you think about that perspective in 2025?
Speaker 2: I don't think [00:07:05] it's accurate, but a good way to look at it is say, Okay, Okay. We've done a lot of [00:07:10] these experiments already in animals. Yeah, and it works. So what happens? [00:07:15] And what happens, the most salient thing that you can [00:07:20] measure in these animals, if they're treated, and the experiments we've done [00:07:25] with sirtuins was genetic intervention, primarily.
But you can also [00:07:30] intervene to raise NAD levels in the animals. And what you see most [00:07:35] saliently is that they're healthier.
Speaker 4: Mm
Speaker 2: hmm. So they move around more at an advanced [00:07:40] age and so on and so forth. And it would be the same with people. What you would see is they would be [00:07:45] healthier longer. They would be less inclined to getting this disease, that disease, [00:07:50] the other disease.
And longevity data is harder to come by because you have to wait till they [00:07:55] die. Right. So most of the animals, we have both sets of [00:08:00] data. Okay. And you get both. You get healthier. And longer lived. And it [00:08:05] makes sense. If you're healthier at the last, in the last decile of life, [00:08:10] it's not surprising that you're going to live longer than an animal that doesn't get the [00:08:15] treatment.
In humans we have mainly the, the beginning to have, because human [00:08:20] data is harder to come by, but we're beginning to get health data. Which is good, [00:08:25] and then we have to rely on these the methylation clock as a [00:08:30] biomarker at this point because there have been no prospective studies, but there [00:08:35] are studies like the INKI ANTI study that I mentioned that were done long enough ago.
That you [00:08:40] can look at data that occurred earlier in the life of this person, like blood samples, [00:08:45] and make projections [00:08:50] that actually align with the real data of what happened to these people going [00:08:55] forward. What is a sirtuin? Well, sirtuins are something we got into when we were studying [00:09:00] aging. Yeah. So we started studying aging in, uh, 1991, and [00:09:05] we wanted to ask, uh, what genes, uh, Control aging.
Okay. So [00:09:10] the system we worked with them was yeast because yeast was simple enough that we [00:09:15] could do what's called forward genetics and look for mutants that live [00:09:20] longer.
Speaker 5: What we
Speaker 2: did, so we did this forward genetics and we got a [00:09:25] strain that lived longer, and we analyzed it, and Yeah, just [00:09:30] bring it in. We're good.
Thank you, Eric. Beautiful. And what it led to is this gene [00:09:35] called SIR2 in yeast. Right. And SIR2 was known as a gene, the SIR [00:09:40] stands for silent information regulator. And [00:09:45] yeah, maybe I will take one of yours. All right. This one is old enough that the paper is sticking to
Speaker: the Yeah, [00:09:50] it's not a good sign. So you want to let this melt up here.
The xylitol will go down. Don't just suck on it. You'll get a [00:09:55] pretty good hit. I'm going to break it in half unless you're a regular nicotine user. I'm not. Okay, [00:10:00] three milligrams. I just use it for the mitochondrial effects and neuroprotective effects at lower [00:10:05] doses. And yeah, just uh, let it sit up there.
Speaker 2: Yeah, this reminds me of Elon [00:10:10] Musk smoking pot with Joe Rogan. There's
Speaker: tobacco and [00:10:15] marijuana in there.
Speaker 2: That's all it is.
Speaker: Hurry up, I'm
Speaker 2: coughing. Although this is presumably [00:10:20] what you gave
Speaker: me is legal. It is absolutely legal and it's, it's not smoking, it's not tobacco. [00:10:25] And having been on the Joe Rogan show. Man, you go right [00:10:30] before the cameras roll. He's like exhaling and you want some if I'm high on your [00:10:35] show, I'm gonna be an idiot.
So I declined. Great. I don't think it did much [00:10:40] good either. I probably wasn't good for him. Um, this is going to do good stuff for your brain, though. I [00:10:45] think you're going to
Speaker 2: like it. Yeah, I do already. Okay. Um, so we got [00:10:50] this gene SIR2. Yep. And the key experiment was if we added an extra copy [00:10:55] of that gene to regular yeast cells, they live longer.[00:11:00]
Speaker 5: So
Speaker 2: that says this gene is a longevity gene. Right. Slows down aging [00:11:05] somehow.
Speaker 5: Mm hmm.
Speaker 2: Okay. And it turns out it does the same [00:11:10] thing. In other organisms.
Speaker: So, could I just do some gene [00:11:15] therapy to add some extra sirtuin genes to myself? Gene therapy is almost impossible in humans. But I [00:11:20] mean, didn't I do it with a full statin gene?
It cost me 25 grand. You don't think it was only good for [00:11:25] two years? No?
Speaker 2: I mean, it's possible.
Speaker: We'll have Liz Paris and you will do a debate here. [00:11:30] Yeah. Kidding, okay. It is hard to do and expensive.
Speaker 2: And there are better ways. Okay. To get to the [00:11:35] same.
Speaker: Yeah. Well then, alright. So, so I
Speaker 2: want more sirtuin activity in my cells.
So, these sirtuin genes are [00:11:40] really important. Slowing down aging, you might be like this fact. Let me [00:11:45] give you a fun fact about sirtuins. So, as I said, we have [00:11:50] seven sirtuin proteins encoded by seven sirtuin genes. Right. Which are [00:11:55] all in the nucleus of the cell, okay? Three out of those seven [00:12:00] genes encode proteins that, like all proteins, are made in the [00:12:05] cytoplasm of cells, okay?
But three of them then go to the mitochondria [00:12:10] and live there. So the, you take NAD. Almost half.
Speaker: You take NAD, your [00:12:15] sirtuins increase, and you take some other stuff too, and then half that goes into the mitochondria.
Speaker 2: That's the [00:12:20] effect. Okay. Will be felt in the mitochondria. Okay. Doesn't that say the mitochondria must be important in [00:12:25] aging?
Yeah, that's a good case. Yeah. Okay. Yeah. So that's the fun fact. [00:12:30] Uh, we can come back to that later, but that was really what first [00:12:35] pulled me into the mitochondria world.
Speaker 5: Mm.
Speaker 2: A lot of people thought that [00:12:40] mitochondria, with no evidence, mitochondria were important in aging, but this, this was, uh, [00:12:45] quite startling.
Speaker: Okay. So that was a really strong piece of evidence for that. I think so. All right. I think [00:12:50] so. Make sure that it's just melting up here. If you suck on that thing a lot, you're going to get a [00:12:55] rapid dose of nicotine. You're going to get pretty happy.
Speaker 2: Well, you know, the [00:13:00] early philosophers and
Speaker: ethicists
Speaker 2: thought that [00:13:05] life should be aimed at human happiness.
I think they're right. Don't you? [00:13:10] I do. And, and, and, you know, in the age of enlightenment and the, You know, [00:13:15]
Speaker 5: 1700s,
Speaker 2: This was the dominant view and that's why people like, uh, [00:13:20] Jefferson and and so on were of, of that school. And that's why the [00:13:25] Declaration of Independence says the goal, one of the goals is pursuit of [00:13:30] happiness.
Speaker: You know, I've studied the Enlightenment because that's kind of how this quest to [00:13:35] understand nature with science came together. And one of the features of the [00:13:40] Enlightenment that we don't talk about very much is the rise of the coffee house. So, during the Enlightenment, [00:13:45] coffee first made its way from Africa to Europe.
Turkey, right? That was important. [00:13:50] Yeah, and they actually tried to ban coffee houses because people were having [00:13:55] intellectual discussions and they were becoming rabble rousers. So, uh, coffee equals [00:14:00] freedom, which is why there's my caffeine tattoo on the arm. But it seems to [00:14:05] play an important role in mitochondrial biology, caffeine's involved, right?
Yeah,
Speaker 2: it's in the mix for things [00:14:10] that
Speaker: are good for your health. So enlightenment equals coffee in my mind. Yeah,
Speaker 2: yeah. So [00:14:15] anyway, so, so I think these sirtuins really set the stage for an [00:14:20] important gene family that affects aging. The second finding we made in the 1990s, the very end [00:14:25] of the 1990s, papers published right at the turn of the, uh, decade [00:14:30] in February 2000, um, is that they require a [00:14:35] compound that cells make, Otherwise, they're dead as a doornail, and that compound happens [00:14:40] to be NAD.
Speaker 5: Mmm.
Speaker 2: And that was the link between [00:14:45] NAD and aging. And what that says is, if NAD levels [00:14:50] decline, if they don't stay high enough, sirtuin activity will fall, [00:14:55] and you will lose this, this break, this uh, repressor. [00:15:00] Of aging,
Speaker: and
Speaker 2: aging will go faster.
Speaker: So, we must keep our [00:15:05] NAD levels at youthful levels in order to be healthy [00:15:10] over
Speaker 2: time.
Well, at least to benefit from this class of proteins, your two ones. Okay. [00:15:15] Okay? And also NAD helps cells make energy, mitochondria make energy. Okay. [00:15:20] So NAD is really important, but this finding to me said NAD is, is going to be very, [00:15:25] very important in the aging process.
Speaker: There's another ingredient that you use [00:15:30] with Elysium, um, And it's related to resveratrol.
So I started using [00:15:35] resveratrol when I was about 23 years old. This is in the mid 90s. But I [00:15:40] switched about 1999 to pterostilbene. And if you're listening to this, you're going, what, [00:15:45] what? It's P T E R O is how that's spelled. And I always thought of it as [00:15:50] resveratrol on steroids. So what's the difference between resveratrol [00:15:55] and pterostilbene?
Well, you,
Speaker 2: you were prescient. I'm not. And, um, got me [00:16:00] excited about so taro is extremely similar
Speaker 5: to resveratrol.
Speaker 2: So [00:16:05] resveratrol has these two fennel rings that are [00:16:10] connected by a short carbon chain with a double bond trans double bond for the [00:16:15] chemists out there. And, um, and it has three hydroxyls. Okay, that's the [00:16:20] all.
in resveratrol, okay? Tero is exactly the same [00:16:25] thing, except three of those OH hydroxyl groups [00:16:30] are O methyl, and that means instead of the hydrogen on the oxygen, there's a [00:16:35] CH3, one carbon and three hydrogens, on it, so it's a subtle difference. [00:16:40] But it tends to make a big difference because it was shown in studies in [00:16:45] cells that you could get the same effects of resveratrol [00:16:50] on the cells, a good effect on the cells, with a much lower dose.[00:16:55]
And the reason is it gets into cells better. So, so it's more [00:17:00] having that carbon, the methyl group instead of a hydrogen, makes it better able [00:17:05] to get through hydrophobic surfaces. And [00:17:10] that can be, you know, in cells or membranes and going through your gut. And get it [00:17:15] getting absorbed into the blood. It's like a delivery system.
It's a delivery system. It's more it's what they say [00:17:20] is it's more bioavailable. Got it. Okay. Okay. That's why we included it. And it's the [00:17:25] second ingredient along with my riboside, which is the booster in [00:17:30] our first product basis. And the idea was you're going to give this double [00:17:35] whammy. Pill that will hit sirtuins in two different ways, and that will be more [00:17:40] effective than either one of them alone.[00:17:45]
Speaker: I think you might have been the first in [00:17:50] our supplement out there. I remember talking about you guys maybe in the second year of the show. I [00:17:55] was. Yeah, I've, I've used it quite a bit. Okay. Question about [00:18:00] delivery systems. So, it seems like you can take most compounds that will accept a methyl group, and [00:18:05] that usually increases their bioavailability, sometimes it makes them stick around longer in the [00:18:10] liver and all that.
But you can also add a phenyl group to things, which makes it really powerful, things like [00:18:15] phenylgaba and whatnot. What's the resveratrol with the phenol group thing called, and [00:18:20] has anyone tested it? I don't know.
Speaker 2: I
Speaker: don't know.
Speaker 2: I want to try it. Yeah, the tricky thing there is the [00:18:25] phenol is pretty big. Okay.
Okay, so, you know, you can do something negative, you can do [00:18:30] something bad by really changing the molecule radically, so it's not the same molecule. So we should [00:18:35] give
Speaker: it to a yeast first.
Speaker 2: Yeah. Okay, we'll do that. Yeah, they don't complain. [00:18:40]
Speaker: And I'm sure by the end of the episode, your mind will have like done all the 3D folding and that, and you'll know the answer, [00:18:45] right?
Yeah. I don't think so, but after 40 years, come on, man. No,
Speaker 2: no, no. All right. [00:18:50] I can't think of exactly a molecule like that in nature.
Speaker: Yeah, sometimes they aren't. I [00:18:55] don't think phenol GABA is out there in nature, but when you take that for sleep, it will knock you [00:19:00] out in a way that GABA won't. So somehow it's getting past the blood brain barrier, but just
Speaker 2: and there are a lot of [00:19:05] compounds where fennel will do something.
There are things called chemical chaperones. And what they do is they [00:19:10] help misfolded proteins to fold better. Okay. And a good example [00:19:15] is a butyric acid with a phenyl on it. Okay. Phenylbutyrate. Oh, yeah, I [00:19:20] take that stuff too, yeah. And, uh, and that is, it will help misfolded [00:19:25] proteins fold better. And misfolded proteins can be normal proteins, but if you, um, have a [00:19:30] mutation in a protein, this could be a heritable mutation.
Oh, wow. Could be a [00:19:35] heritable disease mutation. Mm hmm. Okay there's some evidence that a compound like [00:19:40] that, Okay. Can actually help that protein to fold. Is it ethical to give [00:19:45] a drug like that to people? Well, a, it is if it works and it passes through [00:19:50] FDA tests, so that's a drug. So it would have to go all the RI through all the rigorous testing.
Speaker 5: Mm-hmm . [00:19:55] The
Speaker 2: FDA requires and be safe. So if it's safe and you do a human [00:20:00] trial. And it works, then yes. And in fact, the compound I [00:20:05] mentioned, phenylbutyrate, has, has been given in people. And and, and [00:20:10] it's effective in a metabolic disease.
Speaker: I'm sort of asking in jest, because of course it's [00:20:15] ethical. In fact, I would say it's ethical even if the FDA doesn't approve it, it's probably ethical because their hit rate [00:20:20] isn't so good lately.
But I would I would like to. [00:20:25] Take that and put it into just aging in general. It feels like it's ethical to [00:20:30] give people pharmaceuticals or nutraceuticals or, you know, special lights, whatever [00:20:35] it takes that makes us live longer. And that to not do that is [00:20:40] unethical. But you teach an ethics course at MIT on medical ethics.
[00:20:45] What's your take on the ethics of extending human life?
Speaker 2: So I'll give you both sides. Yeah. And I'll [00:20:50] tell you right away that I'm on the side that says it is ethical. Yeah. Okay. And I think it [00:20:55] is ethical because of this close connection between slowing down [00:21:00] aging and warding off diseases. Okay. And all [00:21:05] of medicine, most of it is based on preventing or [00:21:10] mitigating human diseases.
Okay. And so if you have a compound that [00:21:15] will do that. And by a side effect is it makes you live longer, right? How can that [00:21:20] not be ethical? So that would be my argument. With you 100%. What's the counter argument? The counter [00:21:25] argument is that You look at the species as a whole, numerous [00:21:30] ones, but one of them, one of the prominent ones is, you know, what matters [00:21:35] most for the sake of the species is that we continue to reproduce because [00:21:40] otherwise we go away.
And what's important for reproduction is what happens early in [00:21:45] life, first half of our lives. Okay. And, um, [00:21:50] if you have an intervention that will make you live longer. It's kind of [00:21:55] irrelevant for the propagation of the species. So we shouldn't waste any time on, [00:22:00] on or, uh, energy or, uh, any money.
On that we should be focusing on [00:22:05] diseases that kill people and like cancer and that can kill people early in [00:22:10] life. That seems
Speaker: from that mindset, that seems unethical too, because you would want [00:22:15] Darwinian evolution to keep our, us really strong. So if you're [00:22:20] opposed to longevity therapies, you should also be opposed to public sanitation.
So we could breed [00:22:25] only the strongest next generation and that would make you an asshole. Or am I missing a point here?
Speaker 2: [00:22:30] Yeah. So Darwin would say that, you know, what's again, what's important is, [00:22:35] is the species. Yeah. And so, you know, as long as you have reproduced, [00:22:40] have succeeded in terms of the species.
So it's like an Elon kind of thing. What comes after, [00:22:45] yeah, it doesn't matter so much. Okay. And yeah, that's the other argument against these kind of [00:22:50] interventions is it, it, it goes in the direction of eugenics.
Speaker: Mm. Okay. [00:22:55]
Speaker 2: I know eugenics. I don't, I don't buy into that. I buy into the notion that it's part of [00:23:00] medicine.
Speaker: Got it. If we were to take NAD supplements and [00:23:05] give them to children, they wouldn't do very much because their levels are already high, right? Yeah. [00:23:10] When's the right time to start enhancing NAD?
Speaker 2: That's a good question. I [00:23:15] mean, and I think, I would say the right time is when it starts to decline. And, you know, I don't think we know [00:23:20] that with precision, but somewhere in the middle of life, because by the time [00:23:25] you're, sort of middle age, you know, when you're like age
Speaker 5: 50,
Speaker 2: NAD [00:23:30] is down.
Okay. So you should probably do it at 40 or something. Maybe, maybe 40, maybe even [00:23:35] earlier. 35 ish, 30? I can't, again, we don't have precise data on that, [00:23:40] but, and, you know, if it's really, uh, there are no bad side [00:23:45] effects. Yeah.
Speaker 5: You know,
Speaker 2: why not? And if it's making you, even a, Yeah. Tiny bit healthier. [00:23:50] See, what I think is the way to ask the question is, when does aging begin [00:23:55] conception?
Well, I think, I think aging, you can't say that [00:24:00] aging is happening during development. I think I mean, it could be. [00:24:05] But maybe that wouldn't be a good, it
Speaker: would, it would be one of those very flat asymptotic curves where [00:24:10] there's, it's 0. 1 percent in the first five years. It doesn't matter. Yeah.
Speaker 2: Yeah. So I think when aging, [00:24:15] it's going to accelerate is post reproduction,
Speaker: post normal age of reproduction, which [00:24:20] is late teens.
If we didn't have education and all the stuff we do, right? Yeah. Okay. Something
Speaker 2: like that. [00:24:25] Yeah. So at that point, if aging is starting to go up, [00:24:30] that should be the best time to intervene really. Because, yeah. If you don't, [00:24:35] then you will sustain aging during whatever period you haven't intervened. And so, yeah, [00:24:40] intervening later is still going to work, but it's not going to work as well as if, if you started [00:24:45] earlier.
Speaker: And prevention is cheaper than reversing by orders of magnitude from what [00:24:50] I've experienced in the longevity field.
Speaker 2: But you know, I started late by necessity and [00:24:55]
Speaker: we didn't
Speaker 2: know, and, um, you know, I'm still, I still feel lucky.
Speaker: [00:25:00] I started. Quite early in life because I had many of the diseases of aging before [00:25:05] I was 30.
I had arthritis. I had right, right on the edge of diabetes. I had the chronic [00:25:10] fatigue, the brain fog, and just this whole host of things. Very high risk of [00:25:15] stroke and heart attack because my blood was too thick and just all the bad things. [00:25:20] And so I said, the stuff that's making these old people young is making me as a young person [00:25:25] way more powerful.
I got my health back thanks to the first generation of longevity [00:25:30] researchers. Even like Derek Pearson and Sandy Shaw and all the stuff they were teaching. Uh, and, [00:25:35] and so I'm just profoundly grateful because I got to learn from guys who'd been studying like you had been [00:25:40] even. I remember reading,
Speaker 2: A few years ago, the obituary of Jack [00:25:45] LaLanne, Jack LaLanne.
Yeah, absolutely. Because when I was a kid, he would always be on TV [00:25:50] exercising, right? And he had just, he, he just cut a perfect, [00:25:55] perfect shape. And when he was young, he was sick all the [00:26:00] time. He was overweight and he had a miserable life. So what he did was, [00:26:05] you know, he, he decided that he was going to embrace extra extreme exercise.[00:26:10]
And, um, and, you know, I think in his 80s, he was still swimming [00:26:15] and pulling boats.
Speaker: It's funny that you bring that up. Um, [00:26:20] what I observed as a young man trying to figure out my own health is that there was this [00:26:25] incredible body of knowledge from bodybuilders. There's some of the best biohackers out there.
[00:26:30] Well, what are all the variables I can do? I have a goal and I'm going to manipulate everything. And then I'd [00:26:35] go to my longevity non profit group, and they didn't look like bodybuilders. Like, some of them were on that low [00:26:40] calorie forever, like, I, you know. Calorie restriction. Yeah, not, not a happy place to be.
[00:26:45] But there was almost no crosstalk. And then you'd talk to the neuro guys, and they didn't talk to the other guys either. [00:26:50] And, and then the meditation crowd, they were weird, that's a different conference. But there was some [00:26:55] sort of common element, and all of those seemed like there were aspects of aging.
How much, if [00:27:00] you were to weight this on your, this is your personal beliefs, but you're just a believable [00:27:05] guy. I mean, look what you've done. So you can put, if you have a hundred dollars, right, and you got to [00:27:10] spend it all. Some goes in a meditation, stress management bucket. Some goes in a [00:27:15] nutrition bucket.
Some goes in an exercise bucket. And we'll [00:27:20] say some goes in your supplements and pharmaceutical stuff. Where do you allocate [00:27:25] those resources?
Speaker 2: Well, I think it's more subtle than that. Even.
Speaker: Okay. I
Speaker 2: think the first is you [00:27:30] have to identify the buckets, which you just did now and your [00:27:35] comparison of calorie restriction on the one hand.
And bodybuilders, right? [00:27:40] Okay. And you say, okay, it's kind of similar, isn't it? Except, uh, what [00:27:45] happens is for the people doing calorie restriction. So in animals, it works great. They live longer, but [00:27:50] they're in a very protected environment. Uh, and people who do it, [00:27:55] okay? They're really energy starved.
Yeah, it's not a good place. And so they have low muscle mass. Okay. [00:28:00] And they're somewhat frail and cold, but they also don't have as good an immune system, [00:28:05] which requires energy, so they're vulnerable to infectious diseases. [00:28:10] So, they're kind of, you know, doing it in a way that is exposing other weaknesses.
[00:28:15] For the weight bodybuilders, they're taking anabolic steroids. Yep. [00:28:20] Which I think probably has an optimum. It's kind of a bell shaped curve. Yes. And [00:28:25] I'm sure they're overshooting. Oh, especially the older ones. Yeah, they're crazy stuff. And, [00:28:30] and, and that's going to get them in trouble with cardiovascular disease.
And so, so, [00:28:35] you know, they're both in the right buckets. They're shooting themselves in the foot in [00:28:40] a way.
Speaker: So
Speaker 2: it's the
Speaker: degree
Speaker 2: of magnitude. Okay. Because it's the, it's getting the balance [00:28:45] just right of how much. Yeah. To do it with what intensity and the calorie [00:28:50] restriction. So that's why when we were first studying
Speaker 5: sirtuins,
Speaker 2: one of the first things we [00:28:55] link them to is calorie restriction, because what we found is in in yeast, [00:29:00] if you just lowered the glucose source, which is their food, okay, feed [00:29:05] them to grow.
You can make them live longer, and you could also activate, you can make SER two [00:29:10] more active.
Speaker 5: Mm-hmm .
Speaker 2: Okay. So that led us to think that if you could [00:29:15] activate SER two. Okay. Which is one of the seven, right? Which is one of the [00:29:20] seven SER two. Right. But in east it's, it's, it's the, okay. Anti-aging genes simpler.[00:29:25]
Okay. If you could activate it is there a way you can activate it without lowering the glucose? And [00:29:30] of course, that's what we did when we added an extra copy of the gene. Okay. So in people. [00:29:35] If you could activate the sirtuins, I felt, without the calorie restriction, that would be the [00:29:40] best thing. And I think that's what you would do by boosting NAD.
Makes so much [00:29:45] sense. You're eating normally, okay? And again, if you eat to excess, you will also [00:29:50] undo a lot of good things that you've done otherwise. So I think the best thing [00:29:55] would be to have the right interventions that hit on the right pathways. [00:30:00] In the cells, like sirtuins, okay, and, um, [00:30:05] avoid you know, like, extreme lifestyle choices.
Speaker: So [00:30:10] maybe ultra endurance athletics and CrossFit might be too much [00:30:15] athletic stimulation. What about carnivore versus vegan? Those are both pretty [00:30:20] extreme.
Speaker 2: Yeah, again, I would say there it's I would lean [00:30:25] towards the vegans.
Speaker: Really?
Speaker 2: Okay. I would certainly lean away from red meat. [00:30:30] Why? Because there's lots of evidence that red meat [00:30:35] has a lot of fat.
And leads to cardiovascular disease. [00:30:40]
Speaker: Interesting.
Speaker 2: And I would, I, I would just stay away from it and, and whatever else they feed the animals. [00:30:45] That's not good for you. You're taking in. Yeah. So, so I really believe that. Now, as far as other [00:30:50] meat sources of protein or fish mm-hmm . I eat a lot of chicken. [00:30:55] And fish, and even pork that's lean, pork, it's easy
Speaker: to get [00:31:00] rid of the fat.
You're not doing the saturated fat side of things. [00:31:05] Is, is the red meat thing because of, uh, [00:31:10] like the rare sugars that are in red meat, the way Dr. Gundry talks about?
Speaker 2: [00:31:15] I don't know, I'm not going to say, I'll play agnostic to that, but I know that [00:31:20] the fat and the saturated fat, And red meat
Speaker: is not doing you any good.
[00:31:25] Interesting. And is that like a mitochondrial biology perspective? Or is it because it's escorting [00:31:30] lipopolysaccharides across the gut membrane? Like, look, do we know a mechanism there? Because I, I ended up in a [00:31:35] different camp on that front. And I'm not one of those takedown debate guys. I'm genuinely [00:31:40] curious about how you arrive at the conclusion.
Speaker 2: So they, uh, the fats have been linked to the development [00:31:45] of plaques in your blood vessels. Which are one of the culprits [00:31:50] in cardiovascular disease, because plaques are, you know, and can become an obstruction to blood [00:31:55] flow. Causal or correlational? You find a lot of fat. In fact, [00:32:00] the first thing you see mm-hmm
Blood vessels as a young adult. Yeah. Even if you're [00:32:05] healthy.
Speaker 5: Mm-hmm .
Speaker 2: Called fatty streaks.
Speaker 5: Mm-hmm .
Speaker 2: So the fat tends to, to, [00:32:10] to deposit and the inner linings of your blood vessels.
Speaker 5: Mm-hmm .
Speaker 2: [00:32:15] And those form a nexus for the development of a plaque with, [00:32:20] you know, cholesterol.
Speaker 5: Mm-hmm .
Speaker 2: And, um, [00:32:25] LDL and so on.
That will eventually lead to cardiovascular [00:32:30] disease. So, you know, again, I suppose if you ate the right amount of red meat, which might be very [00:32:35] little, but some, it would be okay. But I think that in the past, [00:32:40] it's gotten, it's changed somewhat. But when I was young, people ate a lot [00:32:45] of red meat. Yep. And people died of heart attacks very frequently.
[00:32:50] Don't they die more of heart attacks now than they did 20 years ago? Oh, 20, I'm thinking 50 years ago.
Speaker: I
Speaker 2: [00:32:55] don't
Speaker: know, I don't know the data from 50 years ago. 50
Speaker 2: years ago, you know, I remember my neighborhood. [00:33:00] And the middle aged men just, just disappearing. [00:33:05] Interesting. With heart attacks, fatal heart attacks.
Speaker: I was a vegan. I was a low fat [00:33:10] guy. And I, I ended up, after I saw a couple of studies showing that [00:33:15] all the plaque when they did, uh, like isotope studies was coming from gut [00:33:20] bacteria. Um, where it was actually, uh, fermentation derived [00:33:25] plaque. So for the past 15 years, I eat almost all saturated fat, [00:33:30] butter, cheese, grass fed meat, and I just did a clearly scan and [00:33:35] we're looking for diffuse plaque.
I don't have any diffuse plaque in the body. Um, I have two [00:33:40] spots where there is, uh, Small amount of plaque, and the [00:33:45] interpretation on that is it's probably from when I had COVID, that there was actually like some scarring there that's in the process of healing, but [00:33:50] everywhere else, there's nothing. I think you're blessed, and
Speaker 2: which means you probably have a good gene or [00:33:55] two.
It could be my supplements, too. You have other supplements, and you're blessed. But for [00:34:00] many people, perhaps most, I think they're not going to have that outcome. They're going to have the opposite [00:34:05] outcome.
Speaker: They also do substantial amounts of olive oil, but not all olive oil. So I always encourage [00:34:10] people, you know, get your lab tests and try something for three months.
Look at LP, PLA2, and if [00:34:15] there's any damage to the lining of your arteries, you're going to see it. And then modulate. Your fat [00:34:20] intake knowing stearic acid is different than palmitic acid and it gets complex just like you're [00:34:25] saying for everything I would
Speaker 2: say to get back to vegan. Yeah, I mean, I think that for me what works is [00:34:30] what would be considered the Mediterranean diet Got it.
Very common and and I for [00:34:35] me I would include the the wine
Speaker: Interesting. So [00:34:40] that's kind of controversial.
Speaker 2: It is controversial right now. It wasn't controversial 10, 20 years ago. I'll tell you [00:34:45] that. So things that change over time. Right. Uh, like, you know, butter versus [00:34:50] margarine. Sure. And so on and so forth.
Um, and when there's a new finding, I, I tend [00:34:55] to kind of, um, be, uh, dubious about it.
Speaker: I think the answer may be [00:35:00] radically different. For different people, which is why having access to your speed of aging [00:35:05] is so foundational. So people could say, all right, fine, I'll be a vegan for [00:35:10] six months and see what there's how you feel.
But then there's what are your markers [00:35:15] do? And if they're broken, keep being vegan. But check them again in a year because you might not like it. I [00:35:20] went about, A little bit more than a year, and I started shattering teeth because of [00:35:25] mineral depletion, probably from excess oxalate, because my biology doesn't handle oxalate well.
And people are like, oxal [00:35:30] what? So, bottom line is, different plants work differently for different [00:35:35] people, different proteins, different fats. But at the end of the day, adequate NAD [00:35:40] levels mean your mitochondria can handle if your diet's not perfect. Well, the important thing about [00:35:45] NAD,
Speaker 2: though, is NAD goes down in everybody.[00:35:50]
Okay, as you age, right? That's kind of a universal. So it's tied to resilience, right? If it's [00:35:55] high. If you're just raising, just counteracting that effect of declining NAD, [00:36:00] and NAD at adequate levels is a positive,
Speaker: that's kind of a no brainer, isn't [00:36:05] it? You want the resilience to eat the french fries, even though you know they're bad for you, because a lot of people are going to do [00:36:10] that.
So if your NAD levels are high, That spells resilience inside the [00:36:15] cells, and that then spells resilience for your whole biological system, right?
Speaker 2: Yeah, I would say with regard to the [00:36:20] french fry question, I also like french fries. For some people, a lot of french [00:36:25] fries would be no problem at all. There are people who handle it, yeah.
Lucky people who have good genes [00:36:30] for that. Although the damaged canola oil might be an issue for even those people, right? Okay.
Speaker: [00:36:35] Yeah.
Speaker 2: For others, if they get the amount of fries they eat just right, they're still [00:36:40] okay. But Many people are going to overshoot for their biology, [00:36:45] and then they get in trouble.
So, you know, the general recommendation would be to kind of, [00:36:50] you know, limit your intake of things like french fries and certainly red meat.
Speaker: I've [00:36:55] on record saying I'm looking at the math. If I was forced to eat french [00:37:00] fries or smoke a cigarette. I've never smoked a cigarette in my life, but I had smoked a cigarette [00:37:05] because the inflammation from that is eight hours and the French fries is 48 [00:37:10] hours and they're kind of similar.
And I know nicotine has neuroprotective effects and would at least probably [00:37:15] be fine after I finished coughing. Uh, so I think I'm an extreme though.
Speaker 2: Well, you know, I [00:37:20] smoked at one very short period of a few months, my whole life.
Speaker: Let's talk [00:37:25] about survival and when you're young. My experience has been, [00:37:30] till you're about 28, you can do whatever you want.
You stay up all night, eat the [00:37:35] pizza, drink five nights a week, and you're gonna wake up around then and [00:37:40] go, You know what? I'm actually noticing that that's slowing me down. And so there's something that [00:37:45] happens in your late 20s that's like the very first little Tingles of aging [00:37:50] and biological limitations.
Is it that we're unaware of it before we're 28 and it's [00:37:55] happening? Or is it that our, you know, our HPA got weak, our ability to make [00:38:00] adrenaline and cortisol went down. What's going on around that time? [00:38:05]
Speaker 2: So, I, I would, first of all your premise
Speaker: mm-hmm .
Speaker 2: I would agree with, [00:38:10] but not, not totally. Okay. Yeah. Explain.
Yeah. If you look at mortality mm-hmm . [00:38:15] Function of age. Okay. So let's say we start at birth here. [00:38:20] Okay. And, you know, it's going up ever so simply, right? And [00:38:25] now you're under your teens and there's a blip, high [00:38:30] mortality. The thing comes back down and it's in males only. [00:38:35] It goes up. It comes down, and then it goes back to it's, you know, accelerating [00:38:40] slowly age.
And what's happening is you know, those are the years of, [00:38:45] you know, young men dying in car crashes [00:38:50] and, uh, shootings and so on and so forth. So there is a [00:38:55] blip. Okay. Okay. But otherwise, I agree with you. It's slow. Okay. [00:39:00] And what's happening, I think, is, you know, aging is happening. That's what I think.
And [00:39:05] I think you're unusually perceptive to notice it at 28. Oh, I was,
Speaker: I'm [00:39:10] really good at pattern matching because I used to have Asperger's syndrome before I react
Speaker 2: to my brain. You had [00:39:15] conditions. I
Speaker: had all those old people conditions, including arthritis, before I was 25. So
Speaker 2: you [00:39:20] were in a in what's called a poised population.
Mm hmm.
Speaker 5: Mm hmm.
Speaker 2: [00:39:25] Okay, you were poised to see a biological effect of aging. [00:39:30] Okay. In fact, in the aging trials, just a little side thing here, [00:39:35] if you do a trial, if you want to measure, is something likely to make you [00:39:40] live longer? Okay. One kind of trial you can do is in what's called a poised [00:39:45] population. So, for example, obese people, right?
They're poised. It would have been me. You don't [00:39:50] want to give them, you don't want the trial to look at them dying or anything. Right. But you can look at whether what you're [00:39:55] giving them is going to ameliorate any aspects of their obesity. For example, [00:40:00] inflammation. Right. That they experience. And that's a really useful trial because those things [00:40:05] that have happened in the obese people at a young age, Right.
Are going to happen in normal [00:40:10] people, or, you know, I shouldn't say normal, I should say, uh, people [00:40:15] unafflicted with the condition when they get older and aging is causing it. [00:40:20]
Speaker: It's interesting, one of the metrics that I'm starting to work with at Upgrade Labs, right, a [00:40:25] longevity lifestyle franchise we're calling it fat age.
TM. [00:40:30] And we're looking at the distribution and amounts of fat correlated with aging. And [00:40:35] it, no, it's not pheno age and it's certainly not what you're doing with Elysium, but it's a very easy to get metric. [00:40:40] This is, huh, there's a curve and where do you land on the curve? And [00:40:45] It seems important to manage that along with everything else.
Yeah,
Speaker 2: I should say, I think the [00:40:50] very first intervention to come out of the Sirtuin's work was resveratrol.
Speaker 5: Mm hmm. [00:40:55]
Speaker 2: Okay, and that was studied in mice. Right. In the lab. And the decisive [00:41:00] experiment To see that it's a good thing was mice fed [00:41:05] a high fat diet, okay? Mice fed a high fat diet live longer, [00:41:10] given resveratrol.
So again, they were poised for you to see an effect, [00:41:15] and you saw it. Now, resveratrol should have worked. really well in humans, but it didn't. [00:41:20] And the reason Why didn't it? Yeah. Well, it's sort of why your intuition led you to [00:41:25] terastilbene in 1999. Yeah. And the reason is it's not so [00:41:30] bioavailable in people.
Speaker 5: Mmm.
Speaker 2: And it's hard to get the dose high enough to do anything. [00:41:35] So it did work in some trials in some conditions, but it was too [00:41:40] spotty. Right. Too sporadic. And it's a fact that for [00:41:45] people to take seriously. Okay. So that's, I think that's why I think you were [00:41:50] really ahead of the curve in, in turning to Terry Stilbean at such an early date.
Speaker: I would like to [00:41:55] say it was because I was really smart. It's because I hung out with the leaders of the longevity movement every month [00:42:00] in Palo Alto doing community education. So I just learned from basically my elders and [00:42:05] said, you know, these guys are smart. I'm going to do what they're telling me to do.
It's kind of the reverse of me hanging out with a tough kid. [00:42:10] Exactly. I feel so lucky that even though I went through all that health [00:42:15] garbage, because I met amazing people and I learned so much and it's been able to, to be [00:42:20] shared. You put this combination that really comes from a wealth of [00:42:25] experience, you called NRPT, which is the Elysium formula of these two [00:42:30] compounds in the right ratios.
Yeah, right. What did the trial show when you run [00:42:35] real hardcore things on that?
Speaker 2: So the first thing I felt we needed to show. [00:42:40] is that it really, we really could raise NAD in a sustainable way in humans. [00:42:45] Because if you don't raise NAD with this, you give up, right? It doesn't work. [00:42:50] And that's a trial you can do fairly easily because you can measure NAD levels.
And [00:42:55] so we did that trial. It was published in Elysium totally Elysium sponsored [00:43:00] trial. And it was amazing, because in one month, you could [00:43:05] see NAD levels rise about two fold. These people were, I think, between [00:43:10] 60, 70 years old, and that age group had already suffered the decline in NAD. [00:43:15] And it came back to just, it came back exactly to where it would be in young people.
Speaker: And how do they [00:43:20] feel when they, when they double their NAD?
Speaker 2: Well, feeling things like is [00:43:25] tricky because of something called the placebo effect. So in that trial, we didn't do [00:43:30] surveys to see, you know, so without a placebo control, control trial, [00:43:35] if you just, you know, give a few people something and say, does it make you feel better?
[00:43:40] Yeah. A lot of them will say yes. Of course. So you have to do a placebo. [00:43:45] Controlled trial and you know, we have a tremendous amount of anecdotal [00:43:50] data from customers now and customers report a lot of things. And so you can say, [00:43:55] well, is that real or is it not real?
Speaker 5: Yeah.
Speaker 2: If you hear something enough, though, [00:44:00] patterns emerge, you think you think it might be real, especially if it's something unusual.
Speaker 5: Yeah.
Speaker 2: And so, you know, [00:44:05] early in the early days, what we heard with basis is that [00:44:10] people were saying it cleared up their rosacea. Yeah.
Speaker: Interesting. Increases in [00:44:15] mitochondrial function can cause a reduction in autoimmunity in studies. Yeah.
Speaker 2: Yeah, but keep in mind you [00:44:20] know, sirtuins do more than that. So three of them are in the mitochondria, but the other four aren't.
Speaker: Oh,
Speaker 2: [00:44:25] let's talk about the other ones besides SIRT2. What, what do those do? So they're all SIRT2 related. Mm hmm. Okay. So [00:44:30] they're all SIRT2 related. They're also to have cert one through seven, seven. Yeah, we have humans. The [00:44:35] reason we're so complicated. One reason is a gene that's present in one, [00:44:40] just one copy in yeast might be present in three, five or [00:44:45] seven copies
Speaker 5: and
Speaker 2: humans, but the seven aren't identical.
They're somewhat different, a [00:44:50] little bit different. They all have the basic activity, but for example, with a mitochondrial sirtuin versus a [00:44:55] nuclear
Speaker 5: sirtuin,
Speaker 2: they're different because they're in a different [00:45:00] neighborhood in the cell. And so they have to have different functions. So we have all these sirtuins in [00:45:05] different compartments and the mitochondrial sirtuins, I'm sure contributing to the health of the mitochondria.
The nuclear [00:45:10] ones are doing something really important. I alluded to it earlier. They affect [00:45:15] silencing of DNA, of the genome, and that's something called epigenetics. [00:45:20] Right. And epigenetics is Very important in aging. It's just [00:45:25] it doesn't get a lot of publicity because it's it's I think it's partly the word.
Just [00:45:30] see people think it's impossible to understand. But it's not that hard to understand. It's very [00:45:35] easy. Basic way to think about it is, let's say you compare your skin cells [00:45:40] to your blood cells. They're pretty different from each other as cells, right? [00:45:45] Yeah. Okay. They have the same genes. They have the same genome.
Exactly. The human [00:45:50] genome. Identical. So why are their cells different? And the reason is, the genes that [00:45:55] are expressed, that are turned on, in a skin cell versus a blood cell, are different sets [00:46:00] of genes. Right. And so that means there has to be ways to keep some genes turned [00:46:05] off. So if all the genes are turned on, In a cell, you've got chaos.[00:46:10]
Correct. There's no cell like that.
Speaker 5: Mm hmm.
Speaker 2: Okay, it's not compatible with [00:46:15] life. Yeah, right. So keeping that straight genes [00:46:20] that are on and genes that are off in the skin cell in a blood cell in a brain [00:46:25] cell. Okay, is very important. And if you lose that fine [00:46:30] tuning cell. That's going to blur things, and that's a part of aging, [00:46:35] and that's, that's called epigenetics, and that's what sirtuins do.
They control what [00:46:40] genes are turned on and off, along with other genes in, in different cell types.[00:46:45]
Speaker: Can I let you in on a little [00:46:50] secret? Sure. The definition of biohacking, when, when I launched it, was the, [00:46:55] Art and science of changing the environment around you and inside of you [00:47:00] so you have full control of your biology. It's just epigenetics, but epigenetics is bad [00:47:05] branding and biohacking is good branding.
But it's literally change this and then change this. [00:47:10] And you have control you didn't think of. And that's why sirtuins, the [00:47:15] stuff you're doing with pterostilbene, with NRPT, with basis, it's [00:47:20] a part of biohacking because you're changing the environment inside your cells, which is epigenetics. Exactly. So that's
Speaker 2: why I think [00:47:25] sirtuins are poised to do this because they can affect epigenetics in the [00:47:30] nucleus.
Okay. Which is so important in aging and in everything, [00:47:35] but especially aging. And you have the mitochondrial ones that can affect the [00:47:40] mitochondria, so, and the mitochondria are extremely vulnerable places because the [00:47:45] way they make energy, okay, you know, we breathe in oxygen, [00:47:50] and we breathe out carbon dioxide.
Yeah. And as a result [00:47:55] of that, we make the chemical energy in a cell, which is called
Speaker 5: ATP.
Speaker 2: [00:48:00] Okay. But, but that means the oxygen is going through a series of, of reactions [00:48:05] that affects their amount of electrons they have attached to
Speaker 5: them. [00:48:10]
Speaker 2: And there's something called reactive oxygen species or ROS produced [00:48:15] along the way.
And they, they're very bad actors. Right? Okay. And they, they [00:48:20] destroy proteins in cells, RNA in cells. Mm-hmm . They [00:48:25] destroy molecules. We need to live. Okay. Now this is all [00:48:30] done in mitochondria to produce tp, right? So the mitochondria are gonna take the biggest hit [00:48:35] from the R oss because that's where they're produced.
Okay, and that's why they're very vulnerable. [00:48:40] And they also don't repair themselves genetically the way your nuclear cells do, right? So one of the [00:48:45] ways they do repair damage is through an enzyme [00:48:50] called superoxide dismutase, which just reverses some of that damage, [00:48:55] okay? And one thing that controls the activity of [00:49:00] superoxide dismutase is one of the sirtuins, SIRT3.
Speaker: Really? Yeah. And when I take [00:49:05] NRPT, does that help my SIRT3 levels?
Speaker 2: Yeah, it will help your SIRT3 [00:49:10] because of the
Speaker: NAD.
Speaker 2: And we have another product, but it's not, it's, it's you know, [00:49:15] basis is really for all the cells in your body. Okay. And, um, you know, I [00:49:20] think it's a really good product. But just to fine tune on mitochondria, a second product is called [00:49:25] Signal.
It's a newer product. Okay, what's in it? So Signal also has an NAD booster. [00:49:30] Okay. Okay. This one's NMN, which is very similar to NR. Right. Okay. But we wanted to [00:49:35] incorporate NMN into our portfolio because it's very [00:49:40] similar to NR, but not identical.
Speaker: I've recommended those both since the first NMN. So [00:49:45] with you there.
Take
Speaker 2: Signal.
Speaker: Um, I haven't tried Signal, no, because you guys didn't send me any, but I did [00:49:50] buy a kilo of NMN from China when the first study came out. But
Speaker 2: the important thing [00:49:55] about Signal is that it has second components. What is it? So, so Basis has a second component, [00:50:00] which is Terra. Right. Still being. And it's called Hinokiol.
Speaker: [00:50:05] Oh, I like this. I wrote about Hinoki in, um, Superhuman, my aging book. [00:50:10] This is really a powerful substance, and most people never heard of it. Yeah, we
Speaker 2: dug deep to find this, [00:50:15] but there's You're gonna send me some of this. Yeah, and there's a good literature. that says that one of the [00:50:20] things Henokial does is it activates SIRT3.
Speaker 5: Mm hmm. [00:50:25]
Speaker 2: Which is exactly what you want to help mitochondria fight against oxidative [00:50:30] damage due to ROS.
Speaker 5: Mm
Speaker 2: hmm. So, that product was developed specifically [00:50:35] to help cells via helping repair [00:50:40] mitochondrial damage.
Speaker: Fascinating. I'm going to predict something. When [00:50:45] people are taking taking SIGNL, the new formula, if you can manipulate [00:50:50] your SOD levels, gray hair, one of the three causes of it, is from an excess [00:50:55] of free radicals and SOD is what quenches them.
So do people see less graying or even a [00:51:00] restoration of hair color when they're doing SIGNL?
Speaker 2: I don't know. We could, I would predict [00:51:05] that based on pathways. We could, we could find out, you know, when you make predictions like that in biology, it's always [00:51:10] tricky. Biology is always more complicated than what you know.
But we can look into that. [00:51:15] It makes sense. What I would say is that certainly tissues that really need a lot of energy, like [00:51:20] muscle, brain, you know, muscle, brain. Right. Okay? It would really behoove them [00:51:25] to have mitochondria that are robust and, uh, clearing up damage [00:51:30] as it occurs.
Speaker: Okay. Okay?
Fasten. Okay, so that's signal. [00:51:35] And There's something else that it's almost boring at this point. [00:51:40] It's methylation and My very first book it was [00:51:45] on fertility and I'm recommending a folinic acid Which is a methyl donor that doesn't [00:51:50] overshoot and there's all kinds of technical stuff In later years, you've seen Gary Brekker talk a lot [00:51:55] about MTHFR and homocysteine and I just tell people look There's a lot of stuff you can measure [00:52:00] But if you can get your C reactive protein, which is, I have an infection somewhere, and you get your [00:52:05] homocysteine, which I have a problem epigenetically with my B vitamins and you can get [00:52:10] some marker of vascular inflammation, I like LP, PLA too, do those [00:52:15] things and you've probably got the big guns for inflammation, which is a sign [00:52:20] of mitochondrial things.
Yeah. So what do you do with homocysteine in aging? Yeah.
Speaker 2: Yeah, homocysteine is a big, a big [00:52:25] player, and it's not well appreciated, I think, out there. It
Speaker: needs to be.
Speaker 2: It really [00:52:30] needs to be. So, homocysteine is produced in our cells as [00:52:35] a byproduct of metabolism, and specifically, uh, methionine biology. [00:52:40] Um, methionine can get degraded to produce homocysteine.
Speaker 5: Yeah.
Speaker 2: [00:52:45] And so, the B vitamins are useful, because they can both [00:52:50] slow, uh, Production one B vitamin can slow the [00:52:55] production of homocysteine from methionine and two others. can promote the degradation [00:53:00] of homocysteine. So, in both cases, you're diminishing homocysteine. One, in [00:53:05] one case, because you're making less, and the other case, because you're degrading it faster than it [00:53:10] does get made.
So, we, we got into this homocysteine from a study that was done at Oxford, [00:53:15] Oxford. Thank you. Uh, University about 12 years ago. Oh, wow. [00:53:20] It was a human study on aging adults. And the [00:53:25] hypothesis of the professor at, uh, Oxford who was doing the study [00:53:30] was that homocysteine was a bad actor. And if you lowered it, you would have [00:53:35] beneficial effects on the brain.
Speaker: So it's not
Speaker 2: just a signal that you have a problem, it's actually a [00:53:40] cause of the problem. Oh, it's a culprit. Beautiful. Okay, that's interesting. So they spent time [00:53:45] showing that a particular concoction of three B vitamins at the appropriate [00:53:50] concentration, and it's much higher than you would get in a normal multivitamin.
Methylated B [00:53:55] vitamins? Or just regular B vitamins? Regular B vitamins. Okay. Folic acid is one. Okay. [00:54:00] I think, um, paradoxal. There's another one, and [00:54:05] Paradoxine? You mean like, B6? Paradoxal? B6. Okay, yeah, okay, got it. B6. [00:54:10] And B12. Okay. Is the other one.
Speaker: Mm hmm.
Speaker 2: No, [00:54:15] B3 is just, uh, niacin.
Speaker 5: Yeah.
Speaker 2: And so, what they showed is that, first of all, it [00:54:20] definitely, so, You know, people have different amounts of homocysteine, and if it gets above a certain [00:54:25] level, it's very bad.
What's the bad level? It's the measurement, they measure it in total homocysteine in the [00:54:30] blood, and I think once you're at something like 10 I think it's mgs per [00:54:35] deciliter.
Speaker: Yeah, I forget the units in the U. S. But I think,
Speaker 2: I think it's mgs per deciliter. [00:54:40] About 20%, 10 to 20 percent of Americans have dangerous [00:54:45] levels, and about 30 percent of people in China.
Have dangerous level. And that leads to [00:54:50] uh, cognitive impairment. So what they did in the study, that I was about to tell you. Yeah, it's interesting. [00:54:55] Is the, the, the lead on the study, is they measured brain volume. In [00:55:00] these people over a two year period, so it's a two year trial and the control and [00:55:05] placebo controlled the placebo group placebo, the intervention group got the three [00:55:10] B vitamins at the appropriate dose and that what they were doing is imaging this became possible only [00:55:15] recently because right imaging got so good that they could measure precisely the volume of the [00:55:20] brain.
Shrinks and that's bad. Okay. Okay. And the measure, [00:55:25] the rate of shrinkage and, uh, and some of the people. It [00:55:30] was much faster than in others. And it turns out that it was the group that it [00:55:35] was faster in is the people who started with high homocysteine.
Speaker 5: Mmm.
Speaker 2: Okay. [00:55:40] So, what happened in the trial is people who took The B [00:55:45] vitamins who had the higher homocysteine, okay, which was about, uh, [00:55:50] I think almost 50 percent of the people showed a massive reduction [00:55:55] in the shrinkage of the brain and their cognitive function was preserved.
So homocysteine is [00:56:00] affecting other things besides the brain, I'm sure. I'm sure, like
Speaker: systemically.
Speaker 2: But this was [00:56:05] easy to measure because you could measure brain volume with the great imaging that we can now do with [00:56:10] MRI. Something like
Speaker: a third of people have genetics where they just [00:56:15] aren't going to be able to process folic acid, right?
So maybe those people in the [00:56:20] study didn't have MTHFR genes, they just had homocysteine? I [00:56:25] don't know. Okay, got it.
Speaker 2: Folic acid alone is going to have some benefit. Right. But it's really the [00:56:30] three vitamins that are going to have Three in combination. Much more potent agent. And so we [00:56:35] developed a product based on that.
Interesting. For the brain called MATTER. MATTER. Matter. Okay. It's so simple. [00:56:40] It's just got a ratio. Those three of those three will be vitamins, and that will clear up [00:56:45] homocysteine problems.
Speaker: I've been managing my homocysteine for a long time [00:56:50] because my longevity practice and I keep it around seven or eight.
[00:56:55] It is a good number. And if it's too low, it's apparently not very good either. Like you don't feel good when it's really [00:57:00] low. I'm so over suppressed. My homocysteine probably isn't good. I don't know that anyone's done the [00:57:05] science on, on the, the right amount. And we know that over 10 is bad. And [00:57:10] just maybe six months ago, I ran one of the Axo panels.
Um, [00:57:15] Axo is the lab testing part of Upgrade Labs. And my homocysteine was like 16. 8. I'm like, [00:57:20] That is not good. What just happened? This is abnormal. So I looked [00:57:25] and I'd run out of one of the supplements that I take. I said, oops, shame [00:57:30] on me. So I started taking it and it's back down right to where it should be.
What was it? The supplement? [00:57:35] It was trimethylglycine.
Speaker 4: Hmm,
Speaker: which is a big has three methyl [00:57:40] groups that you can do and I also added in
Speaker 2: vitamin B12 by the way, it [00:57:45] works on single carbon metabolism. That's what it does. So you might have been [00:57:50] benefiting by that, that mechanism.
Speaker: Oh, it could have been. I also added for linic back in which [00:57:55] I've taken and, uh, What I found was if I took methylfolate, which a lot of people like to [00:58:00] do, that causes muscle cramping throughout the body.
Over methylating is a really nasty sensation. So you want [00:58:05] to really mess with someone, give them like 10 methylfolates and they'll like, It's like the
Speaker 2: horrible, [00:58:10] horrible thing. A lot of these things that have an optimal, so the dose matters [00:58:15] and you can't do things willy nilly. And that's a question I have you know, and I'm, I'm not [00:58:20] saying, Putting you in this group, but the biohackers [00:58:25] do is they get a little bit of information about something.
And [00:58:30] then they apply it in the wrong way. And, um, and, and the [00:58:35] consequences may not be good. So it's, it's really important to like take the information, [00:58:40] but be able to process it in the right way. So you get a product and a dose [00:58:45] that's going to work, but then you have to test it. You can't assume it's going to
Speaker: work.
You have to test it and [00:58:50] the other mistake a lot of humans will make this including biohackers is we have [00:58:55] about 25 different ways of making a decision in our brain and [00:59:00] they're based on energy metabolism, like a really good decision. I spent all day pondering. I did [00:59:05] notes. I did research, took a lot of energy.
And so you wouldn't do that to decide if [00:59:10] you're going to have eggs or not have eggs for breakfast, right? So you make a snap decision, but every [00:59:15] decision, whether it was a good one or not, yeah. They feel correct, [00:59:20] because we're humans, and it's just an energy saving effect. Yeah, well, there's placebo, and [00:59:25] there's also just the basic algorithm is if something is good, more is better.
If something is bad, don't have [00:59:30] any like homocysteine, high homocysteine, bad, make it zero, not good either. [00:59:35] So, What a lot of biohackers, especially when they start, well, if this is good, I'm [00:59:40] only going to do that. And most curves are U shaped or J shaped. Like, they're [00:59:45] not what you think they are. It's not just a linear thing.
Almost always. Yeah. That's the case. And so the only [00:59:50] answer is,
Speaker 2: decide what goal you want. Someone has to test it. Yeah. It has to be tested. [00:59:55] And, and you have to know the right dose.
Speaker: If you had unlimited resources [01:00:00] to run one longevity trial, what would it be?
Speaker 2: I think the trials [01:00:05] that, I mean, I really believe in NAD.
And [01:00:10] so then the question boils down to, well, NAD for what? Okay, so for longevity. [01:00:15] Um, but we're getting indications that NAD may have a lot of [01:00:20] other benefits and other pathways. Uh, ones we haven't discovered yet. Yeah, or ones we have [01:00:25] hints about, but it requires a really proper, rigorous human trial that might [01:00:30] cost, you know, in the millions
Speaker: of dollars.
What's one of those things that you have a hint about, a [01:00:35] hypothesis you would make and want to test about NAD? Okay.
Speaker 2: So, you know, we have a pilot study not published [01:00:40] yet.
Speaker: Elysium is doing this? Okay. On menopause. Oh, this is a [01:00:45] big thing. There's mitochondria tied in with menopause, right? Tell me more.
Speaker 2: It shows that, you know, basis.[01:00:50]
And a small number of people seems to reduce the symptoms of [01:00:55] menopause. Wow, so you just had a lot of guys buy this. Hot flashes, for example. So, [01:01:00] so what do you do in that case? And the limits of the trial are it's [01:01:05] not a standard placebo controlled, Okay. It's what's called an open label [01:01:10] trial, right?
In which, you know, you give people the pill, they [01:01:15] take it and they report what happens, right? Okay. Now that's a trial as a [01:01:20] scientist. You know, I don't find as rigorous as a placebo controlled trial. [01:01:25] It's still data though. It's data, but the people don't know, uh, in a placebo controlled [01:01:30] trial, they don't know what they're getting.
Okay. And so if you see a difference between the placebo group [01:01:35] and experimental group, that really cannot be due to the placebo effect [01:01:40] because they don't know what they're getting. So don't we know
Speaker: the placebo effect is like 32 [01:01:45] percent or something like that? Significant, right? So if you have an open label and 90 [01:01:50] percent of people are getting results, which is way in excess of what you expect from placebo, that's pretty good, useful [01:01:55] data or no,
Speaker 2: it's okay.
It's not, but still, you want to do the gold standard trial, of course. [01:02:00] And, and you want a number of people that is going to pass statistical [01:02:05] muster.
Speaker 5: Mm hmm.
Speaker 2: Okay. So I would want to do the trial with a large number of people. [01:02:10] Okay. Okay. And have it be, you know, blinded. No one knows what they're getting.
People [01:02:15] doing the trial, you know, they, they, who are administering the drugs don't know what [01:02:20] the, whether it's a placebo or the drug, it's blinded all around and the data is, [01:02:25] is, is locked. So the data, no one has access to, can see the data while the trial is [01:02:30] going on, and at the end of the trial, the data is then unlocked, [01:02:35] and The statisticians analyze it to see if, is there a difference between a [01:02:40] placebo group and experimental group trial done data is cannot [01:02:45] be altered at that point.
And, um, that's how drugs hit the [01:02:50] marketplace and big pharma. And I would like to see it done here because that would be a, you [01:02:55] know, a significant improvement in people's lives. [01:03:00] Wow. I.
Speaker: It really would. Menopause, people don't [01:03:05] talk about, especially perimenopause, the economic impact of it. I mean, there's the [01:03:10] suffering for the women going through it, and also, like, their whole families around them.
Like, it's a really [01:03:15] meaningful stressor. Um, a study from the UK said that every year it was costing something [01:03:20] like 10 billion pounds of lost productivity, even. Not even [01:03:25] counting for suffering. So if you can make a dent in menopause with this trial, that's, that's [01:03:30] a big shift. Wow. Yeah. It's
Speaker 2: impressive. So that's one thing.
And, and, you know, there are other things [01:03:35] like that, that, you know, some things we are moving down the road, like ALS, uh, [01:03:40] and trials. From a, a pilot study showed promising [01:03:45] data to, uh, a bigger trial where you'd be able to see, you know, is this thing really likely to [01:03:50] work? And ALS is something where there've been just so many trials that failed [01:03:55] that anything that that produces, um, you know, wouldn't be extremely helpful.
I [01:04:00] tend to look
Speaker: at ALS, MS Parkinson's Even some [01:04:05] weird sleep disorder things, they can be around failure of mitochondria [01:04:10] in certain parts of the brain. Mitochondria are really in the way for the
Speaker 2: brain.
Speaker: Yeah. For [01:04:15] sure. So, so, like, something that helps one of those quite often helps others if it's via a [01:04:20] mitochondrial pathway.
But if it's via some other pathway, then it's not going to do it. So, I, I [01:04:25] would almost want to see a trial where you're like, let's try it on all these, these neurodegenerative diseases, [01:04:30] because it's going to help most of them.
Speaker 2: Right now that's being tried on ALS, as I mentioned, but [01:04:35] also Parkinson's.
Speaker: Beautiful. Yeah.
Speaker 2: And there's a published [01:04:40] paper. On Parkinson's from a group in Norway. Oh, interesting. Yeah.
Speaker: That's because that [01:04:45] part of the brain where the dopamine neurons are densest is one of the most mitochondrially demanding parts of [01:04:50] the brain. So it's like a little bit of a power fluctuation there.
It could be contributing to it, right? It's
Speaker 2: called a phase one [01:04:55] trial, which means it's the initial trial, smallish people, but the data [01:05:00] looks really promising. So we'll see. [01:05:05]
Speaker: All right. You're a scientist. I'm a scientist. [01:05:10] How much of aging is just in our head? The psychological aspects of it.
Speaker 2: Some of it. [01:05:15] So this is something I always like to say.
So my mom, [01:05:20] when, uh, she got older and got more isolated. [01:05:25] And she used to say to me, loneliness is a killer. This is maybe 30 years ago. [01:05:30] Loneliness is a killer. And I said, probably now there's real data [01:05:35] that says, um, That loneliness really does, you know, make end of [01:05:40] life sooner. Wow. So there are things that are, you know, part of it is [01:05:45] structural, the way our society is.
Mm hmm. That older people get [01:05:50] isolated. But. You know, for older people are, you know, I'm not even people old, [01:05:55] old, but people getting older to the extent you can stay engaged [01:06:00] and that can be family, you know, um, try to, [01:06:05] uh, extend an olive branch to relatives, um, [01:06:10] volunteer work, community groups, anything that keeps you engaged with [01:06:15] people, it's likely to be of benefit.
So I, and I [01:06:20] think that's, and that's, you know, I guess like psychological, although it's [01:06:25] going to impact physiological pathways,
Speaker: it certainly does. In fact Dr. [01:06:30] Murthy, a former surgeon general before he became surgeon general was on the show. The only book he ever [01:06:35] wrote was about the epidemic. Of disconnection.
Yes, he should have just for [01:06:40] brand. He should call it the pandemic of disconnection. They would have given him 10 billion to fix it. But, you know,
Speaker 2: [01:06:45] branding if you're young, that's gonna make you more prone. Yeah, drug [01:06:50] abuse. Yeah. And if you're old, it's gonna push you off the cliff. [01:06:55] Very, very
Speaker: well said. Well, Lenny, 40 years of research in [01:07:00] this at one time little known and just rapidly becoming cool field of [01:07:05] mitochondrial research.
Thanks for this curiosity, the 250 papers and for [01:07:10] making supplements with really good science. And I always ask people to come on the show that you got to help out [01:07:15] listeners here. And you guys came through ElysiumHealth. com [01:07:20] code UPGRADE25 to save 25 percent off your first month. And if [01:07:25] you listen to the show.
Order the test to see what your age [01:07:30] is and get the supplements because you're getting 25 percent off, right? Thanks for making the trip to [01:07:35] Austin and I appreciate your patience with my lack of air conditioning in Texas in summer But hey, [01:07:40] that's how it is. That's how it is. You know, they say a little bit of
Speaker 2: stress There you go, you know if it [01:07:45] doesn't kill you.
Speaker: Mm hmm. This is the sauna episode with hormetic stressors. Uh, there [01:07:50] we go And guys, it's upgrade25 ElysiumHealth. com. [01:07:55] This is longevity 101 stuff. You want to do it. See you next time [01:08:00] on the human upgrade podcast.