• njikomes

Leonard Guarente: Cellular Aging, Oxidative Stress, Antioxidants, Life Extension, Health Supplements

Full episode transcript below. Beware of typos!


Nick Jikomes

Dr. Leonard Guarente, thank you for joining


Leonard Guarente 5:20

me. My pleasure.


Nick Jikomes 5:23

Can you start off by just telling everyone a little bit about who you are and what your scientific background is.


Leonard Guarente 5:29

I am a professor at MIT. I've been on the faculty there for a long time, 40 years or so. And my background is in molecular biology, including biochemistry and genetics. I have studied a few different areas of research with my lab. Over the years, initially, we worked in the area of cell biology, and we specialized in the organism of yeast, which are single cells and relatively easy to study, but which teach us broad principles about biology. And we did that for about 10 years or so. And at that point, I got a little bit antsy to try something a little bit bolder. And we decided to make a foray into research on aging. And this was a very kind of checkered past riddled area at the time. And the balance was, on the one hand, it was a area of not not extremely high repute. And on the other hand, there was an opportunity that if you actually did make significant progress, it was a pretty big deal, because there was really not much known about it except descriptive things, comparing old organisms with young organisms and seeing what changes with aging. So that was essentially the approach that had been done in the decades prior to the early 1990s, when we got involved in this. And so we worked in this area for some time. And since my lab was very experienced with yeast, we made the decision, and it seemed ridiculous to some people at the time. But we made the decision to begin our studies of aging, by studying aging yeast cells. And that's what we did. And pretty much the first five or 10 years, and studying aging, we were studying aging in yeast cells. And what we set out to try and query was whether there were specific genes and we expect that a small number which somehow regulated the rate of aging in yeast cells, and we decided to approach that problem by working using an assay for aging in yeast that was not measured by a clock or a calendar. So it was not you were not measuring time, but you are measuring how many times cells divided. Because it was already known that yeast cells had a very limited number of divisions, roughly 20 or so after which they stopped dividing. And what we then did was, watch yeast cells divide under the microscope and count the number of times they divided. And it was about 20 or so. And we wanted to identify variants, which are otherwise in genetics known as mutants, which would be changes in the DNA sequence in the genome of yeast, which would have the effect of allowing that variant or that mutant to divide more than 20 times. Okay, so that would increase the lifespan, if you will, of that cell. And that really took about five to seven years to get through this, that to actually succeed in identifying genes that had this property. And that's So that's it, it was very tedious work in the beginning. But an interesting gene came out that we really have been studying ever since, which is a gene called cert to in yeast. And in, it turns out that this gene is found in pretty much every


organism, or species out there that includes simple animals like worms, or fruit flies, and mammals, such as mice, or humans. So we all have genes that have a similar sequence and encode similar proteins to this yeast gene, which is called cert to and in nature. Collectively, these proteins have come to be called sirtuins because of their similarity to the yeast gene, sir to


Nick Jikomes 11:05

and what does this gene encodes what is the result of protein doing?


Leonard Guarente 11:10

Yeah, so the gene, so that that was what we're interested in. So what the genetics told us was that if you eliminated this gene, from yeast cells, you made their lifespan shorter by about half. Whereas if you gave yeast cells an extra copy of this gene, so they made more of the protein than normal, they live longer than the natural strain, which in biology is called the wild type strain. So that really said that this protein had the ability to regulate the lifespan in yeast, which is this peculiar lifespan debate based on cell divisions. So we started the next period trying to figure out exactly what the SIR to protein does. And we were studying two proteins, one from yeast, which was the SIR to protein, which we purified, and the closest homologous protein from humans, okay, which is a protein called Sir T one. Okay, so these are both sirtuins. They're similar to one another, but not identical. One comes from yeast, the other comes from humans, and we purify the human protein as well. So we have these two proteins in a test tube. And we had some background information that allowed us to focus on process, which is mediated by sirtuins, which is called silencing in yeast. And silencing is a process, which takes a region of a chromosome, where genes can be expressed in this region, and silencing shuts that down, so that the genes are not expressed. So it's a kind of process that results in a portion of a chromosome, just being kind of wrapped up in an inactive state. So it doesn't do anything. Okay. It turns out that that silencing is an aspect of something that has since then become pretty prominent in biology called epi genetics. And so genetics, as started by Gregor Mendel, in the 1850s, is based on mutations that change the DNA sequence of a gene and change the amino acid sequence of the protein encoded by that gene, okay to result in a change in something you can see in the organism. Okay, Mendel's case it was peas, and plants and flowers. In epigenetics, okay. You also have a change that you can see in the organism, but it is not mediated by a change in the DNA sequence at all. It is something B is different from that, which is where the epi comes from. And what it turns out is that it's a process that takes the chromosome and just shuts it down. Okay. And it was known that there are proteins that binds to the chromosome that are called histones and histones are essentially just wrapped the DNA into a ordered string. fracture across the genome such that the histones form a ball of proteins, it's called the nucleosome. And the DNA wraps around that. Okay. And it was a change in the histones, that mediates this process called silencing this epigenetic process okay. And that change in the histones is known to be due to


a modification of the proteins, okay? And proteins are strings of amino acids, okay, and certain amino acids. And the good example is lysine, for example, can also be modified by a tag that can be put on off taken off of the license. And that tag is a very simple two carbon acetyl group that can be put on the lysine or taken off the lysine. So the lysine can be either acetylated where the tag is on or deacetylated, where the tag is off, okay. Now, it turns out that when histones are acetylated, they tend to promote an open structure in the DNA, so that structure DNA around the histones is elongated. And the genes can be expressed normally. However, when the histones are deacetylated, like things are taken off, sorry, the acetals are taking taken off of the license. Okay, that region, which is deacetylated, shuts down and forms a compact structure and renders those genes inaccessible, and they're not expressed. So that was now. Okay, so so a lot of people had before us, try to see if the sirtuin proteins have the ability to remove these tags from the lysine so or go from an open structure in the chromatin to a closed structure, and from the active state to the silent state. Okay, so that would make it an enzyme that would deacetylase Pull off the acetyl groups from the lysine. So people tried to find this activity, the acetylation activity in server two and fail. I couldn't do it. Okay, so that's where we started. And we also didn't see it. But we were, at the same time, interested in whether sirtuins were silencing in a way that was somehow tuned to the metabolism of the cell. So we're also interested in molecules that were involved in metabolism at the same time. Okay, so that brought us to the really the last key point here, which is a molecule in cells that's called NAD. Okay, and NAD is acronym for the chemical name, which is nicotine excuse me nicotine or mind added mean dinucleotide. So it's two nucleotides that are put together. And and we were we were interested in studying whether NAD might have anything to do with this process. And what we found to make a long story short is that cert two had no deacetylation activity by itself. But if we add it to the reaction in the test tube, now we added to the reaction NAD, okay, then it triggered the deacetylation of the protein. So that meant that it was an NAD dependent deacetylase. And that's a very, very long winded answer to your question of what do these proteins, these sirtuins actually do? What is their biochemical or enzymatic activity? They are NAD dependent deacetylases. And that has, that finding has a lot of different implications.


Nick Jikomes 19:48

So so the sirtuins were discovered to be important for for yeast the lifespan in terms of how many times the cells divide, they've got something to do with regulating How wrapped up or unwrapped up DNA is and whether or not those genes can be expressed in a way that depends on this NAD molecule. When we think about the the finding, it describes a nice that, that their lifespan in some sense is the number of times the cells divide rather than time per se. How is that? Would you say that's generally true? Is the same kind of thing true and human beings that that our cells kind of divide a certain number of times across the human lifespan? Or what's going on there?


Leonard Guarente 20:32

Well, I think that it may be true in humans, but for different reasons. Okay, so in in humans, what seems to happen is so we have different tissues, different organs in our bodies, and some have cells that divide all the time. Okay, the got skin, blood. Others at the other extreme, have cells that divide not at all, for example, the brain. And so, for at least some organs in the human body cell division is not at play, because doesn't happen. So that cells don't wear themselves out by dividing. Okay, but they still age. Right? So this kind of process that happens in GE certainly cannot apply across the board. And humans. Okay, so what about those organs that do have dividing cells in humans like the gut, or the skin or blood? are they experiencing the same process? And you know, the answer is, we don't know for sure. But the speculation would be no, because what's thought to happen? At least, I would say one of the most prominent hypotheses for why these tissues like the gut also age, and cells stop dividing, is because of what happens at the ends of human chromosomes, where the ends of all of our chromosomes are kept by a structure that are called telomeres. And what happens in mammals, including humans, is that as cells divide, the telomeres get shorter and shorter, every cell division, okay? Until eventually, they become critically short. Okay? And the cell senses that as essential, it looks like a break in the DNA to the cells, the end of the chromosome, because it has just this little stop now. Okay, and the cell gets a signal, oh, the DNA is in bad shape. I can't divide anymore. Okay. And that's probably the most likely reason that for organs with dividing cells, cells stop dividing.


Nick Jikomes 23:08

And so are those things reversible? Or does it move only in one direction? Yeah.


Leonard Guarente 23:16

So for yeast, we, we never really demonstrated reversibility, what we saw is, we could make cells live longer, so we could slow this process of aging. Okay. But we couldn't take an old cell and make it young again. Okay. And mammals, I think people would have said, the same thing. Until, you know, about 10 or 15 years ago, when it was shown by Yamanaka that you could take a fully differentiated cell of a human, and it could be a young person, could be an old person doesn't matter. And you could reprogram that cell to go back into an a state of that's found in early embryos during embryonic development, okay, and that state is kind of a stem cell, like state, in fact, they're called embryonic stem cells that occur very, very early in embryonic development. And what he did is he showed that by adding a particular cocktail of genes that were expressed into proteins into this old differentiated cell, he could convert it back to Estelle a cell like embryonic stem cells, and they're called iPS cells for induced pluripotent stem cells. So that's Reverse reversing aging at the cellular level. Okay. And the other thing we know, that must be the case is as a species, we knew this forever, we have to be able to reverse the aging process because any species that could not do that would die out very quickly. And we continue to propagate as a species. So something about going through the process of generating germ cells, and having the germ cells make a zygote, which develops into an embryo something about that process as a whole has reversed aging.


Nick Jikomes 25:49

Interesting, and is there. Yeah. So essentially, every time you create a new zygote, you're obviously creating a new organism. That's young. Yeah, exactly. All the way down to the cells. They look and act Young. Are there any? You know, there's a few different places I want to go. But you know, that reminds me of questions related to the, you know, I think everyone understands we inherit our genomes, the sequence of the genetic code from Mom and Dad, can we also inherent, excuse me, inherit any of these epigenetic modifications? And is there anything so even though, you know, when you create the new zygote, you're you're sort of restarting a brand new organism in the young state? Are there nonetheless, ways to inherit, like if your mother and or father are older, and they have perhaps accumulated mutations or epigenetic modifications in the sperm or the egg? Can that type of thing lead to heritable consequences for the offspring?


Leonard Guarente 26:54

Okay, so certainly, genetic changes will always be heritable, they'll always be inherited. And so that, you know, as a rule, if you have progeny from older parents, those progeny are more susceptible to genetic to inherited genetic changes. So from dad, you know, sperm spermatocytes, the precursors of sperm replicate continuously. And so, an older person has had sperm cells that have undergone more DNA replications, and have had more chance for mutations to occur. And so there's a higher probability of mutations being inherited, and the progeny for mom, the oocytes don't divide during growth, and development, and adulthood, but they're sitting around, so things can happen, and damage can occur. And we know that birth defects, many due to chromosomal abnormalities go up with the age of the mother and the newborns. So those changes happen, but epigenetic changes. I think there's not, it will first of all be pretty hard to show that experimentally, as opposed to a DNA change, we just read off the sequence of the DNA. And I think the evidence is, you know, at best preliminary as to whether epigenetic changes could be inherited. The other problem is, you know, epigenetic changes are pretty much the slate is wiped clean during the formation of the germ cells. I mean, that's that's kind of thought to be the mechanism by which you can get back to youth again, is, is to do that. So that would say you would not expect epigenetic changes to be inherited, generally. And I think the jury's still out on that question.


Nick Jikomes 29:20

When we think about some of the key players here that you mentioned, the sirtuins and NAD and things, what is the the natural course that those molecules take throughout the lifespan of the average organism? Are they decreasing or changing in some way over the lifespan? And if so, what what actually drives that?


Leonard Guarente 29:41

Yeah, that's a very important question. And so for the sirtuins let me give a little bit more background. Humans have seven of these proteins, and they're encoded by seven different genes. They're all related to one another, but they're not identical. They're different. and they all have the same enzymatic activity that I mentioned earlier. They require NAD and they deacetylase, histones, and other proteins in cells. Now, the seven are different in a few different ways. The main difference is the spread across different parts of the cell. So three of them are in the nucleus of the cell. So in the nucleus of the cell, they can deacetylase. They have substrates, if you will, or targets that include the histones, as I mentioned, which are on the DNA and in the nucleus of the cell. But it also includes proteins that regulate transcription, so called transcription factors that turn genes on and off in a gene specific way, and those are in the nucleus. And those can be deacetylated by the nuclear sirtuins, okay, and three sirtuins of the seven human proteins are in the nucleus are T one, six and seven. Okay, three others are in a specific organelle in cells, called mitochondria. And that's it's a very provocative thing, actually, because mitochondria make energy for the cells and energy in cells, comes in a chemical called ATP. And the ATP is produced by mitochondria. So the fact that three of the seven sirtuins are in this one tiny space in the cell, I think, is at least suggesting that mitochondria and energy production, production might be especially important in the aging process. And mammals. Okay.


Nick Jikomes 31:53

Yeah, that's, that's interesting. I was just talking with someone about mitochondria, actually. And we got into some aging stuff. So as far as the question of why sirtuins would be in my mitochondria, is it because the mitochondria have their own little mini genomes? Are they doing the same kind of DNA modifications that they are in the nuclear genome?


Leonard Guarente 32:15

I don't think so. I don't I mean, I think that certainly the mitochondria do have their own tiny genomes. But what from what we know about the sirtuins that are there, and I think the most prominent one is called 33. In the mitochondria, is that it's it's the acetyl ating enzymes, in the mitochondria proteins in the mitochondria that have enough that either are involved in metabolic processes in the mitochondria. And the main one that seems to be a target of 33 is the degradation of fatty acids to the oxidation of fatty acids. In the mitochondria were the enzymes that catalyze oxidation of fatty acids are substrates for 33 to deacetylates them and that turns them on that makes them more active. The 33 would upregulate fat destruction in the mitochondria and that produces energy. Of course, when you degrade fat, that's one way you produce ATP. Another thing that the 33 deacetylates in the mitochondria is an enzyme that removes that fixes oxidative damage to proteins in the mitochondria, okay, that's called it's called the enzyme is called superoxide dismutase or sod. And sod is deacetylated by Sir T three inside the mitochondria and that increases the activity of sod. So that would give it a mitochondria greater capacity to repair any damage that is accumulating, which may also slow down the decay of mitochondria and the aging of mitochondria. So in the mitochondria, I think there are two things at least going on. One is they're involved in metabolic reactions, such as the degradation of fat. And secondly, they themselves get older and more damaged as we get older. And both of those processes tend to be counteracted or regulated by search II three, one is to upregulate the degradation of fat and the other is to increase the repair capacity of the mitochondria. So you might imagine, then, that with this NAD dependent set of proteins, the sirtuins you can maintain healthy mitochondria for longer. You If you keep those proteins as active as possible, and you might also have a beneficial effect of degrading excess fat to exchange fat for ATP.


Nick Jikomes 35:13

I see. So if these sirtuins are NAD dependent, I think an interesting question is, to what extent does do any D levels change throughout the lifespan or, or even throughout like, say the day? sleep wake cycles, diet, things like that?


Leonard Guarente 35:29

Yeah, that was your original question. All that I just said was background to answering your question. So what NAD changes are extremely important in the picture here. And the most important thing about NAD levels is that they seem to go down as we get older, we lose about half of our NAD during aging, and that's going to have a really disastrous consequences to the activity of the sirtuins, and any other process in cells that requires NAD. So, you know, maintaining NAD levels would be, I think, a very important way to stave off some of the effects of aging. And there's a lot of data to back that up in the laboratory. So rodents, for example, can be made to live longer if you boost their NAD levels. Okay. So that's a really important finding. And at least part of that effect is due to sirtuins, because if you deactivate sir T one one of the sirtuins this effect is ameliorated. I'm sorry, it's abolished. So I think that NAD decline is probably a very important aspect of human aging. And, you know, this was really the, one of the very early underpinnings of Elysium when the CEO Eric market Tulia, and I first started talking about 10 years ago, about ways that a company could start to utilize some of the new findings that were coming in, regarding the aging process.


Nick Jikomes 37:43

And so I'm going to those those mouse experiments where you were where people were able to extend the lifespan of rodents to questions, there are a How did you actually increase NAD levels in the animals? Was it through dietary supplementation or engineering a specific kind of mouse? And B, how, what is the magnitude of of life extension that was able to be achieved?


Leonard Guarente 38:07

Yeah. So the simplest thing would be to just feed NAD to the mice. Okay. The problem with that is NAD itself is a compound that does not enter cells, it can't get into cells. So it can't raise NAD in cells if it can't get inside. So what was done is to use molecules. So the way cells make NAD is through a series of enzymatic reactions in cells where that you start with a small building block, which is nicotine amide, or nicotinic acid. And enzymes make it bigger and bigger step wise, until you end up with an ad. And so what's done is you take one of the intermediates in the middle of that pathway, okay? And there were two intermediates right in the middle of the pathway, one is called nm N, and the other is called an R, okay. And the Enderman stands for nicotinamide mononucleotide the NR for nicotinamide right beside and if you add those compounds, they are taken up by cells. So what you can do is you can feed compounds into the middle of this pathway, which will then interact with the enzymes that carry out those terminal steps in making NAD and that will raise NAD levels and cells. So that's what was done it was to give these compounds either and our nn to mice in the drinking water or in the food, okay and then measure to see that NAD levels were raised and they are and then to see what happens and what happens is They live longer. Now, yes. How much longer? So it turns out in mice, it's you can, various genetic interventions can make them live longer, but only by about 10 or 20%. That's really the best anybody has done. In mice. Another thing that will do that is by restricting the food, and the process, that's called calorie restriction. That's been known for about a century now. And again, they'll live longer by up to maybe 30% or so by that intervention. Okay. And the effect of the NAD supplementation, you know, is of that 10 or 20%. Nature, an extension of lifespan? And, and,


Nick Jikomes 40:47

you know, doing doing lifespan studies in humans, I imagine is difficult or at the very least expensive, and requires a lot of patience. But is there anything that's been done in humans? Any studies that might suggest that something similar could be true?


Leonard Guarente 41:06

Well, I don't think so. Not yet. And the problem is exactly what you say that, you know, who's gonna wait to do a human study. So what you can do is you can try to find some kind of surrogate for how long someone lives. And that's what people have been looking for, for a long, long time, they've they're called biomarkers of aging. And if you had a biomarker of aging, then you could simply look at that biomarker, and that would tell you the biological age of the organism. And you could measure that and see if you slow down its progression, and not have to wait the entire lifespan, to see whether there's been any effect. So that's been one of the holy grails in the aging field is to find a biomarker for aging for a long time.


Nick Jikomes 42:09

And are there any good biomarkers in humans?


Leonard Guarente 42:14

What's happened? I think, this in my opinion, isn't in the past decade or so. There's been a very important biomarker, that's, that's been found. And it's, again, it has to do with a modification of an important molecule. In cells. In this case, it's the DNA and its DNA methylation. So DNA tends to be methylated at some positions, where you have a C and A G nucleotide residue together, so C, phosphate G CPG. Okay, and you get methylation on the C residue that happens at various sites across the genome, maybe, I don't know, maybe a million total sites across the entire genome. And what's become available is the ability to very accurately assess the methylation status of all of these residues, which is a combination of chemicals that can distinguish between the methylated C and the unmethylated C, and cut the DNA at the one and not the other, and DNA sequencing. So you can tell where this has occur. And, and so doing you can assess simultaneously, the methylation of many, many residues across the genome all at once in one experiment. So that was what was done initially by Steve Horvath and his colleagues was to just look at the methylation of DNA, okay, in various cohorts of people that were involved in human studies of different kinds, okay with so that there were biological samples available. So let's say blood of these people. And what they did was to assess methylation status across many of these sites in the genome, okay. And they asked whether they could see a pattern of methylation, that changed in a very characteristic way with the age of the person providing the sample. Okay. And they used and what they did is you just train the computer to the task of finding these methyl sites that changed characteristically or monotonically. With aging of the person in question, so let's say the older the individual, the more methylated, that C was, okay, so it goes from an a young person being unmethylated, in a middle aged person, partially methylated. And an old person, fully methylated, let's say, and the technology is such that you can actually make those determinations, okay. But you need the computer and machine learning to then go into that data set, and actually find the relevant methods that you could survey in this way, and come up with a score that will tell you the age of the person. So that's what they did. And in the initial study, so about a decade ago, there were some three to 400 methyls specific sites now in the genome and, and assessing those methods gave you a readout of the age of the person. Okay, so that's not what people were, people were thinking about something much simpler when they were thinking about biomarkers of aging, right. But none of those simple things really worked. So here's something that looked like it worked. And, you know, you could program the algorithm to do this task. Okay. So that I think that's now been elaborated on quite a bit in the last decade. And people have really, I think taking advantage or start are starting to take advantage of this technology of DNA methylation assessment. And, you know, at Elysium, we got very interested in this some, some number of years ago, to see if we could make this work in humans. And rather than require blood, we could do it with saliva. And that's actually works. And it's a product that Elysium offers called index.


Nick Jikomes 47:26

So there's a way for scientists to take a biological sample for people and look at the DNA, but they're not looking at the sequence of DNA, they're looking at the pattern of these epigenetic modifications on the DNA. And that tends to tell you something about the biological age of the person. And my understanding is, you know, part of the point of this is the biological age as, as you, as you see it in these methylation patterns, is not necessarily going to be equal to the chronological age


Leonard Guarente 48:00

broadly, as well, right, so you'll see if you look as a function of age, you will definitely see a relationship between chronological age and this biological age, there'll be similar, okay, but they won't be exactly the same. And they'll be matched in a straight line, going, age versus methylation status, okay. And each person will be a little bit off that line, some will be right on it, there'll be average, but those that are off it are interesting, because that means that their biological age is different, you know, may not be extremely different, but is somewhat different from the chronological age. And so a test like this, you know, you can impute a rate of aging for that person. So a person that's right on that line, okay, would be aging, exactly. Average, okay, in the population. And you could call their rate of aging as one, okay, someone whose methylation status showed a biological age younger than their chronological age, you know, might be re aging at a rate of, say, 0.9. And, of course, that's desirable.


Nick Jikomes 49:21

How, I mean, if you took, you took a random sample of a bunch of people, how many, how many, what percentage of people will tend to be very high, high off of that line, whatever. What you know, however, we define that,


Leonard Guarente 49:38

I think, if you took a random sample is what they did in the original experiments, right? The way the line is drawn, right, the line will be average. So it'd be the same number of people above and below the line by the nature of the beast. Okay, now, we've noticed and customers of Elysium that there's a slight skewing I saw that there are more people than would be expected that are aging more slowly than you then you would expect in a sample that size. Okay. And, you know, the way we interpret that is maybe, you know, we our customers are kind of self selected as people who are very health conscious, right? And in aggregate, would would show a slower average rate of aging compared to the general population.


Nick Jikomes 50:33

And can you talk about how this product works a little bit more so. So if someone purchases it, like, what is it physically that they're doing? And then what does the output actually look like that they see in the end?


Leonard Guarente 50:46

Yeah, so the product would be, it'd be not terribly different from other products out there like 23 and me, or ancestry.com, where you get the product, you create a sputum sample, and you mail it off to our labs. And the sample gets analyzed. And the data gets sent back to the customer, extremely simple, with, you know, a lot of information to put things into context for the customer. And so I think it's really it's a cool part. I think it's really cool, though, that it now potentiate, it allows you to do other things. So for example, our first product, which was based on the research I talked about earlier with sirtuins, and NAD is called basis, okay, and it has two ingredients in it. One is an NAD booster, this thing and are it's one of the ingredients. And the second ingredient is based on research that shows that there are compounds that specifically activate one of these human sirtuins called Sir T one, which is a quite important one. Actually. It's a nuclear sirtuin. And the original studies show that one of these activators are 31 was a molecule maybe some of your listeners would have heard of called resveratrol, red wine, the red wine molecule. Yeah. And there's stat a lot of studies have been done. And resveratrol, since David Sinclair originally showed it could activate 31. And in rodents, Resveratrol has really good effects on the health of the animal. It really is. Amazing molecule. And the thinking 15 years ago was that this was going to be wonderful for humans. And a lot of people including myself, were taking it at that time. But it turns out that in humans, it's so called bioavailability is not so good. So it's very hard to get an adequate dose of resveratrol in humans. And so we knew all that 10 years ago, so we opted for a more obscure compound that comes from blueberries, not grapes, which is structural analogue of resveratrol. Okay, so it's similar as a molecule but with some differences. And we had noted in the literature that even in animals in the laboratory, it seemed to work at a lower dose than resveratrol, which says it's more potent. And so we think that this is a version of resveratrol that is more bioavailable, and much more likely to have beneficial effects. And people it's called terrace Dobby, with a P T at the beginning. And so that's the second ingredient in basis, this combination of NAD boosting which should raise the activity of all seven semitones along with terrorists still being which should buy a different mechanism activates 31. We thought that was probably from what we knew at the time, and would still be true. We'll give you the best shot of maximizing the activity of the sirtuins especially against forces of nature that are causing NAD levels to decay. Mind and deactivate them as we get older. Okay, so that's the product. That's the rationale behind the product that contains two kind of synergistic compounds that give you the best shot of activating sirtuins and impacting aging favorably. Okay, so now you want to, what we're interested in doing, I just gave you a little teaser about this is to ask is, can we use these two products of index DNA methylation product and bases? The NAD sirtuin product? Can they play off one another? Okay. And so, one thing we've done is we've looked at,


we had samples of people from one of the studies that we've done, actually, where we could take those samples and do both the index test on the people and also measure NAD levels in these people. Okay, so these people have not taken basis, they just, it's just people out there in the population. And we found that there was this relationship in that the higher, so we all have different NAD levels are not going to be identical, right? That's determined by who we are. And the higher the NAD levels, what we found the pattern was the higher the NAD levels in these people, the lower their biological age, as determined by index, which is really good, I think. And so it, I think, establishes credence for the idea that there really is a relationship between NAD and aging in humans. Okay. So the next step, which is a study we have started to do, is to ask, okay, so what happens to somebody, if we measure their biological age? And they start taking basis? What happens to it? Means so this gets back to something you asked much earlier about reversing aging. Okay, can you reverse it? And, you know, that's a study, that's going to take time, because now it's that's the so called longitudinal study, where you're following the same people over a prolonged period of time. So we don't know the answer to this yet. And my suspicion is, you know, we started this a few several years ago, like three years ago. And, you know, we started looking at the data and my thinking is, we got a confound, that occurred in the timeframe of that study. And for this week, you know, we just simply ask our customers, if they're interested in opting in to something like this, where we simply, you know, at baseline, when they before they start new customers, before they start taking basis, they do an index test. And in a year, after taking it, they do another index test, okay, it's that simple. But what intervened in that year was COVID, and isolation protocol, and change in lifestyle and habits. And we suspect that that was a major contract, that will probably be shown that COVID changed the rate of agent. And people, I really expect that to be found. So we very much are interested in getting good data on this question, but we don't have it yet.


Nick Jikomes 58:56

Interesting. Given everything, you know, everything that we know about aging so far, do you think it's possible in principle, that one day, we could basically put an end to aging to be effectively immortal, such that the normal aging process doesn't happen? And the only way people would die would be if there was some other kind of disease or accident or something like that?


Leonard Guarente 59:23

I do. I do. And, you know, I would have said no, up until as recently as five years ago, and I did say no, anytime I was asked that question. But I've reevaluated and I think that at some point, you know if if civilization continues to advance in the way that it has been, and nothing catastrophic happens to the world, that it will be possible. Part of the reason for saying that is that you know, you can't and achieve these little bits of success with things like ener D intervention, okay. And you know, many important discoveries start with something that sort of barely works. And then you make it better and better and better. Okay. And the other thing is relates back to another topic we discussed, and that is that it seems you can reverse aging at the level at the level of individual cells by converting skin cells, let's say, of an adult animal back into embryonic stem cells. Okay? And if you can do that, make that complete reversal, right? Why not? Why shouldn't you be it be possible to make a little bit of a reversal and at least enough to stop aging in its tracks? Okay. And there's been some papers published in mice, that will lead you to believe that this might be possible in humans. And it's a little bit that you can do things in mice that you can't easily do in humans, of course. So this, this process of turning cells back into stem cells, that was developed by Yamanaka involves putting into those cells, four different genes. And those four genes, when they're expressed, will turn the cells into embryonic stem cells. Okay. And so in mice, of course, you can make transgenic mice, we've added genes into the genomes of the animals. And so what was done is to put those four genes in into mice in a way that you could turn them all on at the same time in all the cells of the mouse, okay. And initially, when they did that, in the first set of experiments, what do you think happened? Tell us that got cancer, I say, and the reason I got cancer is these embryonic stem cells, remember, this is the early embryo, which has to grow a lot. And these embryonic stem cells are very rapidly growing cells, I say. And if you culture embryonic stem cells, they grow like gangbusters. Okay, that's like you're, you're growing a bacterial cells that grow so fast. Instead of just do this in an unregulated way, won't do that, in fact, it'll do the opposite of what you want to have happen. So what they then did was to figure out a way to control their expression, these four genes, so that you can give the animal short pulses of intermittent expression, she'd give them a pulse, wait a few weeks, another pulse, wait a few weeks. And when they did that, they reported elements of reversal of aging, and the animals, which is a very striking finding. So you know, there's just been a few papers at this point in time on that. So I think we want to wait and see and assess this more completely. But it at least raises this this possibility that this is a strategy that could work now in humans, of course, you can simply, you know, start mucking around with the genome in this way. So you'd have to find some other way to skin the cat. But, you know, those are technical problems and not problems in principle.


Nick Jikomes 1:04:06

Well, another thing this makes me think of is, you know, questions related to the brain, which, which I wanted to talk about. So, you know, even if you could reverse aging, through soothe through some of the means that that you've been describing for us, you know, if you were to, you know, your neurons are really weird in certain ways that that we touched on a little bit earlier, they don't divide, and yet our brains do age. And not only do you want to preserve longevity and have youthfulness in terms of the functioning of your mind, but you also couldn't you know, even even if you would want to even if you could just sort of revert health of your neurons back to a stem cell state to rejuvenate them because you will lose all the information that that makes you you and that that is your life. So how do you start to think about aging in the brain and how, you know, is there anything known about how to preserve the function of neurons are prevented from decaying as quickly as they normally do?


Leonard Guarente 1:05:09

That's it's a difficult challenge. So the first question is what actually happens in the aging process of the brain. And years ago was thought that we simply lost neurons that neurons start dying, and the number of brain cells goes down. And that's, that's how the brain ages and consistent with that, people found that the volume of the brain shrinks with aging. And so that fit this neat idea that you just lose brain cells. And since they're non dividing, once you lose a cell, you cannot replace it. Okay? Now, however, that's probably not exactly correct. Okay, and probably more important than the loss of nerve, so neurons are lost. But in particular, in neurodegenerative diseases, and the loss of neurons really it, it tends to, there's a lot of overlap here, between normal aging in the brain and disease induced aging, but in Alzheimer's, there's neuron neuronal loss. But in normal aging, it probably isn't. And it's probably more a matter of just shrinkage, at every level, in the brain, at the cellular level, at some ultrastructural level, but not at the level of the neurons actually die and disappear. So you have to preserve more than just the neurons in the brain, you have to preserve the connectivity of the neurons, which are connected at synapses that are due to processes that extend from the neuron, which is where really the information lies in the brain. So it's a very difficult problem to think about. We can begin to address some of this. So again, you know, we've been interested, you know, I'm interested in the brain myself. And Elysium, has been interested in this for a while. And so one study that I think is a very good study out of Oxford University, studied aging in the human brain and subjects. And it was monitoring aging, by brain volume, which was determined by imaging. And so the study really is leverages advances in brain imaging technologies, which is gotten quite good and quite quantitative. And so it was a two year study, and they could clearly demonstrate significant shrinkage in the brains in this poised population that they were looking at the poise population was, I believe, people in their 70s who had mild cognitive impairment, MCI. So they were, you know, at a point where they were losing brain function, perhaps a little bit faster than ordinary people, which made the study doable. And so they could see shrinkage in the brain. Now, there was some information out there that there was a bad actor that's produced that's causing at least some of this shrinkage, which is called homocysteine. Okay, and what you could see is that there's a relationship between levels of homocysteine and people and brain shrinkage. And so it was thought that if you could reduce homocysteine levels in people, you could also mitigate the brain shrinkage. And it turns out that they showed that the right combination of three B vitamins of all things at the right doses, which tends to be much higher than the doses you would take an A vitamin pill


could reduce shrinkage and people brain shrinkage over this two year period. And the reason part of the reason is that I don't remember the exact details of this but one of the B B vitamins, I believe it's B six, B nine and B 12. One of them promotes the degradation of home homocysteine and the other to retard the synthesis Have homocysteine so both have an effect together of lowering homocysteine levels in these people. And so that's, that's an interesting finding. And, you know, we got involved with David Smith, who conducted this study a while ago, and based another product at Elysium, called Mater, on the exact formula of what they were providing these people. Now the only thing they should, the only limitation of the study and the people is that showed that people who also had unusually low levels of omega three fatty acids, didn't respond well, to the B vitamins, they didn't have, they didn't have an effect. And so it's thought that, you know, in order to get the benefit of this, you need sufficient levels of omega threes. So we put an omega threes into the product, so everybody taking the B vitamins will also be getting a dose of Omega three. So that's, you know, I think that that's an interesting product, because it's based on on human studies, and can impact the brain in a way that we think is meaningful, that is to say, the volume of the brain.


Nick Jikomes 1:11:27

So what So what are all one liners? What were all the ingredients in that product?


Leonard Guarente 1:11:32

So it has the three B vitamins B, six, B nine, which is folic acid, and B 12. At the appropriate doses?


Nick Jikomes 1:11:43

And what are those doses compared to like,


Leonard Guarente 1:11:46

they're higher, they're much higher. I don't I don't remember the details, but they're much higher, I say. And for those people who might not benefit, by virtue of having low omega three fatty acids, which is in itself, not a good thing, omega threes are helpful. There's an Omega three supplement in there.


Nick Jikomes 1:12:10

I see. So so that one that's called matter. That's like the brain product, you've got one called basis, which is basically the NAD product that we mentioned earlier. And you've got a couple other ones what what are those? And what's, what's the thinking behind the ingredient list there?


Leonard Guarente 1:12:28

Yeah, one of the newer ones is called signal. Okay, and that's related to bases. Okay, so the NAD booster in bases is something called nr, nicotinamide riboside. And that's essentially a half of an NAD molecule. You have the nicotine amide nucleotide, and a ribose. That's nr. And a man is one step further down the chain. And it's the nicotine amine and the ribose with a phosphate on it. So it's one step closer to NAD. Some people think some people favor nicotine in mind, over nicotine in my driver side, although in animal studies, they both seem to work equivalently. Okay, but there's, you know, there was a paper published on an MN fairly recently showing that it had the ability in humans of making insulin work more efficiently. That is to say, increasing insulin sensitivity, which is thought to be a good thing for health, so we wanted to have a product that had enemies in it. And then we found so one of the other interesting targets that, you know, I've been interested in for a long time. So Tara's still being targets are T one, as I said earlier as resveratrol. But there's this important sirtuin in mitochondria, sir T three that we think will be important in maintaining mitochondrial integrity and health with aging, if we could keep it active. Okay, so the NAD Booster will help with that. But if we had a more specific molecule that could target it, that would help even more. And so the literature informed us of something a molecule called honokiol which is reported in several different labs to activate 33. And so again, that's something we got very interested in and obtained a very good source of it. And that's the second ingredient in in signal. So we think signal will have an effect that will be more targeted on mitochondria in aging, and energy production. Things of that sort, perhaps fat degradation in mitochondria. So let's get on the metabolic side with bases.


Nick Jikomes 1:15:00

So you mentioned earlier, I think an important thing to talk about is bioavailability. You mentioned, for example, Resveratrol is a very interesting molecule that does really cool stuff, but it's not particularly bioavailable. And that was why you guys were using this other thing called Terra stilbene. Which is more potent? Are the ingredients in all of your products reasonably bioavailable? Or do you add, add something to it to boost the bioavailability? Because I know that a lot of my understanding is a lot of supplements out there. Not in every case, but in some cases, you know, it might say it's got 500%, your daily value of whatever, but you end up absorbing very little of it. So so how do you think about bioavailability?


Leonard Guarente 1:15:44

Yeah, we're interested in bioavailability, in all cases, and you know, so I think that in the products we've discussed, the compounds are relatively bioavailable, whether they're not. And we're really interested in technology, which exists in which the compound is essentially encapsulated, in vesicles, to make it more bioavailable, and I think, you know, the vesicle technology, again, it's one of the things that I think has really taken off, in fact, the RNA vaccines that deliver RNA to cells work, because the RNA is first encapsulated in vesicles. And the actual vaccine is the vesicles. That will be stable, okay, in the blood, and will then be able to fuse with other members, the membranes of cells to deliver their contents to the cells. And so we're applicable in a number of the products we're thinking of, that are under in development. We're thinking of starting to use this technology to increase bioavailability. So yes, I do think it's an important issue in any of these products. And I think it's one that will become increasingly utilized by us down the line.


Nick Jikomes 1:17:12

And, well, I am just curious to, so you say you co founded this company called Elysium, which is making these products. You know, on the one hand, I can imagine one thing that prompted you to do this was just research and the relevance of what you were learning about aging, to making these kinds of products. But what made you want to start a company as a scientist, I think most scientists I've met, aren't inclined to do that.


Leonard Guarente 1:17:36

Well, first of all, I think it's MIT is supportive of their faculty also being entrepreneurs. Okay, so there's a supportive environment that we have. And a lot of my colleagues at MIT start companies. And in fact, I've been involved in companies in the past, most recently, before Elysium, I was involved in a sirtuins company called Sirtris with David Sinclair, and Christoph Westfall was co chair of their SAP. So, and since the start of Elysium, started, been a founder and another company, that's a kind of a drug development company to target 36. Another important sirtuin in the nucleus, but it's really highly focused on clinical drugs and developing drugs on 36. So I think that, you know, it's basically, for aging, you know, there was all this work that been carried out over a long a long period of time, that was just beginning. Make a blueprint for how you could take this and develop it into something that could benefit health. Okay, and so it's, you know, a very attractive prospect to try to do that. And to see, you know, Can we can we, first of all, find out this, will this work the same way and people and secondly, have the satisfaction of actually being able to impact human health with such a company. The other thing I liked about the concept was really Eric marketeer Lee's idea that, you know, on the one hand, at the time, we initiated our conversations about 10 years ago, you know, there were these supplement companies, which there were many. And the quality was was really frankly, not not great. And some of them didn't even have in the product, what they claim was in there. And if they it was in there, it was almost certainly something that didn't do anything. And so we wanted to make sure that we had have products of high quality and thought that if they really worked, if we could assure and do the testing in humans to back up the preclinical data that they really work that it would actually start to form a space between the supplement companies on the low end. And the drug companies here, classical drug companies that there's a space in the middle, that was an opportunity space to have compounds that really worked. But that could be delivered to customers quickly because they were natural. And so they didn't have to go through the kind of FDA testing and approval of a novel compound drug. And that was an exciting possibility to have this platform, be a platform company, that was not a sample company that would be able to essentially have a rapid timetable for development and testing and delivery of products direct to consumer online, in an efficient way. So you know, there's kind of a lot of attractive features about the company. For me, it's novelty, to prospect for saying that, yeah, this aging research, really lead to something and targeting aging is really good thing for health.


Nick Jikomes 1:21:26

What are I mean, I know the aging field is really booming right now. What do you think are, you know, what are one or two like big, outstanding questions in aging right now that you think we'll likely know the answer to in the next few years?


Leonard Guarente 1:21:42

Well, if it's something that's that's really there's a lot of studies now on senescence cells was this area called Cell senescence. And cell senescence is when cells stop functioning, doing their normal function, but they don't die. So they hang around. And that's thought to be a bad thing. And it's thought that if you could take those cells and kill them, eliminate them. It's much better than having them hanging around. And so there are companies out there, a lot of them. So I think we're gonna know about this quickly, that are developing compounds that can selectively kill a senescence cell. Typically, the senescence cells I mentioned earlier that when dividing cells divide, and their telomeres get sufficiently short, right, they got a signal that a damaged signal, okay? And they stopped dividing. They can also get that damaged signal, not just by telomere shortening, but if the DNA actually does get damaged, as the cells get old, and they stop dividing, but they don't die. They just sit there. And so these companies are developing these Sena lytic compounds, compounds that can lyse senescence cells. And there are, you know, a lot of tremendous amount of activity in that field now, which is why I think, in the next few years, in a very short timeframe, we'll we'll know the full potential of this area of aging research that you can impact aging favorably by targeting not an old organism, but old cells in the organism. Interesting. Yeah.


Nick Jikomes 1:23:38

Well, Leonard, are there any final thoughts you want to leave people with or or anything you want to emphasize from our conversation?


Leonard Guarente 1:23:46

Well, you know, I think I would like to leave people with the idea that we've learned a lot about aging, and the past three decades. And typically, in research, the benefits of the research lag from the time of the research itself, and this is we're seeing this in cancer, where incredible information emerged about human cancers from the 1970s through the, you know, the 2000s, but very little in the way of treatment with the exception of childhood cancers. And in some cases, diagnostics, for cancer, but medicines lacked for cancers, but I think that that's starting to change now. Because a lot of work has been done to take advantage of the basic science. And the same is going to be true in aging. Research, okay. But it's staged, you know, about 30 years later than cancer research. So I think people should take heart that there has been progress. And that there will be remedies not to eliminate aging. But to impact it in a way that we can stay healthy longer, and keep doing what we'd like doing for a longer period of time. So I think that's one take home, I would like people to have. Another is that you know, I think that there's kind of a seamless continuum of the academic research environment, and the world of companies where you want to go, if you can be on a path that starts with a simple experiment in the laboratory and follow that all the way to human studies. It's very satisfying thing. There's a personal statement. And, you know, it's been it's been great to be a part of that all along the way.


Nick Jikomes 1:26:15

Dr. Leonard garantie, thank you for your time and everything that you shared with us. Thank you.


Transcribed by https://otter.ai


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