FoundMyFitness - #010 Dr. Aubrey de Grey and Dr. Rhonda Patrick Talk Aging

Episode Date: August 13, 2015

Dr. Aubrey de Grey Dr. Aubrey de Grey is a biomedical gerontologist and the founder of the SENS research foundation which aims to find technologies that can repair the various types of damage that occur during the aging process. In this episode, we discuss... 00:00:00 - Introduction 00:02:27 - How to understand aging 00:08:14 - Epigenetic modifications accommodate cellular aging 00:18:24 - Inflammation is a double-edged sword  00:24:00 - Parabiosis has the potential to slow aging  00:31:35 - Lifestyle factors can only extend lifespan so far 00:36:49 - Future of Crispr/Cas9 in aging research 00:40:56 - Utilizing pluripotent stem cells from the placenta You can find Aubrey on Twitter at @aubreydegrey, and his foundation at www.sens.org. If you're interested in learning more, you can read the full show notes here: https://www.foundmyfitness.com/episodes/aubrey-de-grey Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello everyone. In today's podcast, I interviewed Dr. Aubrey de Grey. Dr. DeGray is founder of the Sends Research Foundation, which aims to prevent and reverse aging by finding technologies that can repair the various types of damage that fuel the aging process. In this episode, we discuss what those types of damage are, how aging results in a decrease in the capacity to repair these types of damage, what role epigenetics plays in the aging process, how people age at different rates, how chronic inflammation drives aging, some of the very interesting research that's been coming out, showing that factors found in young blood can repair damage when infused into older organisms, the role of nutrition in aging, the advent of new highly precise gene therapy technologies like CRISPR, and other exciting new emerging techniques like that of induced pluripotent stem cells.

Well, I think Aubrey and I do come from slightly different schools of thought on some of the finer details. I respect his role as an agent of change in how people, view the inevitability of aging. Finally, this episode of the Found My Fitness podcast is sponsored by people like you. So if you find great value in any of my podcasts, videos, articles, or newsletters, please consider signing up to contribute $5 a month, which is right around the cost of a latte these days. I have a genuinely amazing array of ideas bouncing around in my head that I'm anxious to get out and recorded blasted out to you guys, including in-depth videos on topics like

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right over to the support page at Patreon, p-a-t-r-e-on-com slash Found My Fitness. And now on to the podcast with Dr. Aubrey de Grey. Patrick here. In this adventure of the Found My Fitness podcast, I'm in Mountain View, California at the Sends Research Foundation, and I have sitting here with me Dr. Aubrey Gray in the house. Aubrey is a biomedical gerontologist, and he is founder of the Sends Research Foundation. And as far as I know, the Sends Research Foundation has taken on quite an ambitious goal, and that goal is to help prevent and cure aging. And I think that Aubrey, sometimes refers to aging as a disease, and so I'd like to talk a little bit about that.

But thank you for being here, Aubrey, and can you please tell us a little bit about the Sends Research Foundation? Certainly. The SENS Research Foundation is a biomedical research charity, so we're a 501c3, which means taxpayers can get tax benefits if they give us money, and we do research into the diseases and disabilities of old age. And I'm a little bit cautious in using words like cure and disease in relation to aging because we have to remember always that aging is, you know, it's a side effect of being alive. It's like it's the consequence of the accumulation in the body of various molecular and cellular changes that are inevitable consequences of what the body does to keep us alive from one day to the next. Those changes are things that I call damage.

And that damage is harmless for a long time because the body is set up to tolerate a certain amount of it. But of course only a certain amount, which means that eventually this damage exceeds our tolerance and we start to decline both mentally and physically and that's what the diseases and disabilities of old aging are. So when I talk about cures and about disease, I'm always a little bit careful. I think that the oversimplification that most people make with regard to the difference between diseases on the one hand and aging on the other hand is extraordinarily damaging oversimification

because it makes people unjustifiably over-optimistic about the possibility of curing age-related phenomena that they do think of their diseases, let's say Alzheimer's or cancer or most cancers or breast or whatever, but it makes them also over pessimistic about medical advances to prevent and preempt the aspects of age-related ill health that they don't think of as diseases, like loss of muscle or decline in function of the immune system or whatever. The best way to think about this is that all of these things are part and parcel of the same phenomenon. They are interdependent but nevertheless individual aspects of the accumulation of the

and cellular damage in the body, and the only way that we're going to bring them under control is by developing a panel of interventions that we can use to periodically repair those various types of damage, and thereby leave the overall abundance of damage in the body below that threshold, such that it's harmless. Right. So let's dig a little bit more into these types of damage, because I talk quite frequently about damage myself. And so, you know, typically when I think of aging, I also think of, you know, the degeneration,

the accumulation of damage and degeneration of tissues, of cells as a consequence of the accumulation of this damage. And at the same time, the inability of our capacity to repair damage, to prevent the damage, also declining. So it's sort of like this imbalance, imbalance that begins to have more damage accumulating and less capable of repairing that damage, as you mentioned. Okay, so I think I actually would like to stop you there for a moment because a very important thing that an enormous number of even gerontologists tend to overlook is that this change in the balance

between damage and repair has to be caused by something, right? You do indeed get, in old age, a more rapid creation of damage and less rapid removal of damage, repair of damage, and thus you get an accelerated accumulation of the overall amount of damage. But why? The answer is because of the damage that was accumulating early in life, throughout life, even starting before we're born, that we could never repair at all. That is the clock of aging. It's the accumulation of damage that we simply don't have any genetic capability to repair

even when we're young. When that accumulates, it does two things. It accelerates the creation of other damage, and it also impedes everything about the body, including the damage repair mechanisms that we have. So we get less good at repairing the damage that we used to be good at repairing. Yes, that actually makes perfect sense. The accumulation of this damage is that we do not repair. We simply cannot repair during our youth.

We'll eventually either damage the DNA inside of our cells, and that will change the function of certain genes, maybe possibly repair genes or genes that help us deal with this damage. they may, you know, change the function of the cell itself. So the cell might become more stiff and that changes the way the cell is functioning or they may change the way proteins are, you know, the function of proteins because now proteins become aggregated and all sorts of changes happen. But in addition to that, it also may lead to epigenetic changes, which also can change

the expression and function of genes. And so I think that putting it that way does make sense. Well, actually, you bring up another. important point, especially with your mention of epigenetics. Because epigenetics is terribly fashionable within gerontology right now. Can you explain what epigenetics is? Epigenetics basically is the study of the changes that happen in cells, whether as a result of aging or as a result of anything else, that cause differences in which genes are turned

on and which genes are turned off. So typically these will range from things at the DNA level itself, methylation of cytosines, for example, up through modifications of histones, these proteins that DNA is wrapped around, up through higher level changes to the packing of chromosomes and to chromatin. You know, an awful lot of different things change the behavior with which a cell actually decides which proteins to express and which ones not to. Let me just center up real quick. And for those of you that don't know what express or turn on or off, it just essentially

is mean what he's referring to is that when a gene is turned on or if it's expressed, active, it's doing the function it's supposed to do. If the gene is turned off or not expressed, that just means that the gene is there, but it's not doing its function. It's almost as if it's not there. But here's the thing. When you see a change late in life, you always have to ask yourself, is this change happening as part of aging, or is it happening as an adaptation to part of aging?

Is it happening, in other words, to minimize the pathogenic consequences of some other change? And epigenetic changes in aging are pretty much entirely that latter thing. There are adaptations that are good for us to make the best of a bad job, namely the non-genetic things that are happening elsewhere. We know this simply because they are coordinated. When we look at tissue in bulk, when we look at lots of cells all at the same time, and we ask what's happening in terms of the gene expression changes, what we're seeing is a coordinated response.

It's got to be coordinated because otherwise it wouldn't be happening in the bulk of cells on average. So it's bound to be an adaptation. It's genetically programmed. It's happening because the cells know what their environment is, whether in charcellular or extracellular, and they're responding to that environment in the same way that they might respond to an infection or to inflammation or whatever. The only way you can actually ask questions about epigenetics that are meaningful with regard to actual aging rather than adaptations to aging is by looking at individual cells. If you look at individual, individual cell, single cell analysis, then you can quantify the noise, the amount of variation

that's happening without any kind of genetic direction. And we're actually doing that. We have had a project for a few years now in the Albert Einstein College of Medicine in New York, looking at precisely this. We're looking specifically at methylation rather than the other aspects of epigenetics, and we're asking does the amount of epigenetic noise in various tissues, is a lot of, in various issues increase with age, working in mice. And the hypothesis that we are pursuing is one that I put forward some time ago now, which

is essentially that, no, it won't, or at least not to a detectable degree. And the reason it won't is because the quality of DNA maintenance and repair, whether genetic or epigenetic, is driven in the evolutionary sense by the need not to die of cancer before you've reproduced. Cancer is by far, in my view, the biggest problem of DNA repair and maintenance because it can kill you with just one cell going seriously wrong in the wrong way, whereas anything that doesn't have to do with the cell cycle has to affect an awful lot of, a high proportion of the cells in a given tissue before it starts to be pathogenic. And that means a lot of cells.

Yeah, so this is all very interesting. Have you, are you familiar with the work that's come out of UCLA from Steve Horvath, I think. So he's shown that from multiple tissues from humans, blood cells and also different, you know, biopsies from different samples, that there's a pattern of methylation that appears to be specific to age. And, you know, it's so precise that, you know, researchers can look at this methylation pattern from, for example, lymphocytes taken from a person, and they can identify the person's age plus or minus four years with 96% after.

Okay, so let me talk about that actually. Yes, I know Steve's worked pretty well and I've discussed it with him. And actually a lot of people have oversimplified what he's been doing and what he's seeing from this. So you're right, there's this extraordinary correlation, R-square of 96% that he's got. He found this particular set of CPG islands of things that change during age in terms of their methylation that change so uniformly that you get this amazing R squared. Now, what does that actually mean? Well, first of all, you've got to remember that actually if you look in the adult part of life, let's say 23 to 70 or 80, then the R squared is much lower. It's like 70% of that.

Secondly, you've got to remember is that that's a good thing because it means you've got some variation to actually work with. If you actually really had something totally linear, then first of all, it wouldn't tell you who's aging more quickly. and who's edging more slowly. But secondly, it would tell you that your signature is the list of the least important things in aging, the things that are just trundling on in a trajectory that was set during development because evolution hasn't had the faintest motivation to stop them trundling on. Well, what I found interesting from the research was more the clusters of genes that this

was involved around, and they were DNA- Kind of, kinder, but that's always dangerous. I was actually involved in the very early days of the gene ontology and I always had doubts about whether it would be misused and I feel that it is being misused in some ways here. I think that one, well, you know, one, it's very hard to factor out the multiple hypothesis problem when you're using that kind of analysis of go terms. you've got to ask yourself how many different types of gene, whether it's in terms of function or process or whatever, and how many, what proportion of those genes are affected.

It's terribly, terribly easy to run with the first thing you see when you halfclose your eyes, when you look at that kind of data. And I think a lot of people have been doing that. But I'll do what I'm interested in with regard to Horvath's work and related work. What I'm interested in is when they have looked not at the enormously good R-square, but at the variations from the R-square. That's why I said that it's good that the ask-winds not so high if you look at adults. Thing there is that then you can actually ask questions like, does the subset of the population that are changing that signature of that group of methylation sites more rapidly

than average, do they actually exhibit age or a hypotology at a younger age, things like that? of function in some other way that you can measure even as a relatively young age. And very recently, just a few weeks ago, there was an extremely interesting paper that came out of a group in New Zealand where they had done exactly this question. They had basically looked at a, I can't remember how many people they looked at, but they did a longitudinal study over, if I remember, rightly 12 years. And there were early adults here, we're talking, I think the ages were something like 26 through 38.

And they looked for this kind of variation. If we can combine that kind of analysis with the kind of methylation analysis that Horvath has developed, then I think we'll be able to ask some very intriguing questions about the predictability of age-related ill health. But now I want to finish my answer by talking about what this means for our work. And this is actually really important because a lot of people overlook this. It's terribly, terribly fascinating that some people age more quickly than others and some species age more quickly than others.

And the whole of gerontology for the more than a century now has been essentially founded on the idea that if we understand that variation really, really well, we might be able to translate that variation into some kind of therapeutic regimen, to turn fast ages into slow ages. And that, you know, I wouldn't object, that would be great, but we've got to remember a couple of things about that approach. Number one, it doesn't work so well if you only apply it late in life. Because it doesn't slow down the accumulation of damage rather than repairing damage, which is what we're all about. So that's bad enough. We'd like to help people who have misfortune to be in middle age already or maybe older.

The other thing is, no one's actually had any success in this. Why not? Because metabolism is really complicated. Messing around with this vast network of undocumented spaghetti code that keeps us going from one day to the next, you know, the idea of stopping it from doing the thing we don't want it to do, the creation of damage, without also stopping it from doing things that we need it to do, you know, it's crazy. It's never going to happen.

So I really don't think that even if we learn plenty by these methods, that it's going to have all that much impact on the development of actual therapies. What about some of the more recent methods? For example, the CRISPR, you know, where this technology, where now I'm going to totally oversimplify this for people, but the ability to specifically target a gene and clip it out and replace it with another gene or a version of the gene that's more active or less active, depending on what it is you want. I think that this new technology, CRISPR, for example, dramatically changes a lot of things

because, I mean, even if we look at, for example, centenarians, semi-centenarians, which lived to be about 105 or semi-supercentenarians live to be 105, and then the super-centenarians, which are about 110 plus. A recent study came out from, I think it was Tokyo and Newcastle, I think. I don't know if you're familiar with the study, but essentially what the study did, and it was the largest cohort of the semi-superior centenarians and the super centenarians. And what they found was that they looked at a variety of different biomarkers, so they looked at inflammatory biomarkers, they looked at lipid profiles, glucose, they looked at in in in in

So when your immune cells no longer are living and dividing, they basically sit around and they're not dead, but they're doing more damage because they're producing more inflammatory things that are damaging other cells. So it's like spreading more nasty stuff around. They looked at immunosinensens and then they also looked at two limit lengths. And then they also looked at like diseases. And then they looked at, you know, organ for like liver function, kidney function. And so anyways, they're correlating all these factors. And what they found was that inflammation was the only thing that drove aging in all the groups. So inflammation, the higher the inflammation, the higher, you know, the risk of death of non-accidents. You know, so age-related diseases, cardiovascular disease, cancer. And this was true for all the groups. But what was really also interesting was that to the centenarians, there was a positive correlation between between inflammation and immunosinensensis,

which was essentially lost in the super centenarian group. And I don't know why that is, but the immunosin essence, so essentially the inflammation went up, and then the supercentenarians, you know, as the inflammation went up, they died. There was a positive correlation. But the immunosiniscence seemed to stay around the same for whatever reason.

So in my mind, I think, you know, well, we know that these supercentenarians, that's possibly around a 25 to 30% increase in human lifespan. So human lifespan in the United States is average around 79 years old. If we could live to be 115 and live to be healthy, that's fantastic. So we know that it can be done with these supercentenarians, and we know that there's a lot of genetic factors that are playing a role on this. I mean, obviously, you know, these people have lower inflammation

compared to non-centenarians. They also show that. And so an inflammation is upstream of all. lot of damage. It's upstream of the damage that's damaging DNA, proteins in the cells, lipids, you know, et cetera, et cetera. So if we can use CRISPR technology to go in and replace, you know, say, give it more anti-inflammatory, you know, capabilities. And this has been shown also in mice. I don't know if you've seen this study, but NFCAPAB, which is a gene that produces a protein that regulates a lot of other genes that are pro-inflammation. So,

cause inflammation, but it also has an anti-inflammatory component to it. And when you take away that anti-inflammatory component and put it in mice, what happens is every time there's an immune response, every time inflammation happens, which leads to chronic damage as you talk about, there's a low-level inflammation and it drives aging prematurely in mice. All right, so big question there. Yes. Let me sort of a fairly big answer.

But let me start with a very simple thing. clear that inflammation is a double-edged sword. That we need it, the reason we have it, if anything that's genetically cut it, that hasn't just mutated into oblivion over-evolutionary time, is because it's good for us. It's because it's an essential component of how we survive infections. However, there are certain aspects of age-related damage accumulation, which, because they are only age-related, are not very interesting to evolution. And therefore, evolution has not taken the trouble to improve the precision of the inflammatory response, so to discriminate between things that the inflammatory response can actually help with,

namely the elimination of infections, and things that the inflammatory response actually exacerbates, namely the accumulation of damage that is not an infection, like oxidized cholesterol or whatever. So that means that, yes, it's likely that, it's my surprise to us, that when you look at a very very elite population, the population that lived to 10510, then they will overwhelmingly have a weak inflammatory response because that is the only way that they will have been able not to succumb at the age of 80 or 90 to atherosclerosis or Alzheimer's, which are definitely driven partly by the inflammatory response. However, what also needs to be taken into account is that plenty of people aged 80 and 90

and 100 die of infection. So, yes, these people got genetically lucky because they didn't get an excessive immune response, inflammatory response to those age-related problems, but they also got environmentally lucky in that they didn't die of infections. Or maybe they just had a really strong adaptive immune system that compensated for the weak environmental response. And so on. So, you know, these are all trade-offs here.

And what it adds up to is that we cannot conclude that it would necessarily be a good idea to take people in their, let's say, 60s or 70s and damp down their inflammatory response. What about bump up their anti-inflammatory response? In amounts to the same thing. If we're talking about the strength of the inflammatory response as opposed to the strength of other aspects of the immune system like T-cells and B cells, then we are engaging in a change of a trade-off. We are giving people less, we are reducing people's risk of rate, well, likely rate of progression

know that's risk, or arthritis and Alzheimer's and such like, but we were also increasing their risk of dying pneumonia, simple effect. And the best way to deal with this is to find a best of both world solution, to let people have the strong inflammatory response that they need in order to be protected well against infections, but to fix the problem of mis- of maladaptive activation of the immune response. And what we're trying to do is exactly that. not by changing the inflammatory response itself, but rather by changing the targets. Ultimately what's happening in atherosclerosis is that the inflammatory response is being activated

by the accumulation of indigestible waste products, specifically oxidized cholesterol in macrophages in the artery wall, which turn into foam cells and generally make cells around them angry. If we could, if that didn't happen, if we could get rid of that oxidized cholesterol, then it wouldn't matter at all, how to turn into fom cells and then. Or how strong your inflammatory response was, you would not get atherosclerosis. Same for Alzheimer's. Ultimately, Alzheimer's has an inflammatory response because the stuff it's reacting to, it's amyloid and town and so on.

We can get rid of those materials, stop them from accumulating to a pro-inflammatory, to inflammation triggering level, then we won't get an inflammatory response, even in people with a strong inflammatory genetic profile. Has the SENS Foundation considered using some technologies that are sort of already present in the body? For example, you mentioned Alzheimer's disease. And recently this glymphatic system has been discovered where now when we sleep, we know that cerebral spinal fluid squirts up into our brain and literally washes out the amyloid

plaques and other buildup of these extracellular aggregates that are in our brain. Has the SENS Foundation thought of any way to use that system? We're looking at it. We're very interested in all ways of getting rid of molecular garbage, whether the garbage is intracellular or extracellia and whether the getting rid of is destroying it on site or flushing it into a place where it gets destroyed in other ways. You know, we're into all of this thing. We keep our eyes very open and our mind's very open with regard to what's going to work.

That's really, that's good to know. What about the new, I find this very interesting, the paribiosis where we can, you know, take, I mean, scientists, can take blood from a young animal and transplanted in an old animal and essentially reverse some biomarkers of aging in multiple organs. Yeah, it's very exciting. We're actually funding in postdoc at Berkeley working in this area in one of the top labs in this area. Of course, paribiosis itself is not a therapeutic vitamin.

We're not going to, I mean, I presume that you would not be too keen to... Right. But it's definitely a great way to make discoveries. And it, of course, leads to alternative versions like plasma exchange and phoresis ways of altering, of taking things out of the old blood or putting things into the old blood, so as to achieve the same effect that parabiosis would. Of course, in order to do that, you need to know what to take out or put in. And a lot of the problems that parabiosis research faces at the moment is that that's really

laborious and tricky to find out in any kind of systematic way. the few hits that people have had so far in terms of factors that seem to actually have some kind of causal role like GDF11 and so these things, you know, were found more or less serendipitously. And everyone knows that there's likely to be a number of others out there, perhaps very likely to be ones that are more central to the effect, but which have not been found just because they're a little more counterintuitive. So I envision, you know, if these factors can be identified, GDF 11, growth differentiating factor 11,

was thought to be possibly playing a role in causing, you know, muscle stem cells to divide and proliferate and possibly in the brain as well. But others have not been able to confirm that. Yeah, what's the space? That's going to run and run. Yeah, I mean, I'm not sure. I mean, all I know is that I'm excited about the research in general. And whatever the factors are, I envision possibly making recombinant proteins. I mean, people are, you know, using EPO or with their poitin, I mean, human growth factors.

So it's not the same sort of deal. The big thing that needs to be taken into account here is that the factors that change in their abundance in the blood during age, whether up or down, and that may have an effect in terms of if you like, transmitting a, transmitting pathogenic damage from one place in the body to another, those things are, first of all, they're not necessarily just proteins. We also have to worry about cells, the fact that you have, you know, changes in the relative abundance of different types of T-cells, for example. And there's also small molecules, glutathione, things like that, you know, things that may

simply not be amenable to rejuvenation by measures like plasma exchange, but only by something like paribiosis. Then we would have to look at a different model. But I want to also emphasize something I just alluded to a moment ago, which is that we are talking here not about mechanisms whereby damage is created. We are talking about mechanisms whereby damage is transmitted from one part of the body to another. After all, that's what the circulation is.

It just takes stuff from one place to another. It doesn't create damage. The damage comes from somewhere. So we always need to be looking out for the possibility that we can find the cells that are the source of the changes in the blood and change those cells back to a rejuvenated state. By that means, reduvenate the blood. Well, I think that the source of damage in the sense of the circulation, the blood cells, you know, and the immune cells in the blood are just the,

that, you know, when you activate macrophages, they dump out hydrogen peroxide and all sorts of reactive nitrous species. Yeah, that's not really what I'm talking about. I mean, I'm talking about, for example, well, let's say the thymus, for example, the thymus itself shrinks, as we were saying earlier, and that is largely responsible for the fact that in an older person, there are few naive two cells and more memory to itself. You know, if we can fix the thymus, then we fix that problem. And, yeah, I can make many other examples.

Yeah, that really makes sense. Something else, you know, talking about this damage, and, you know, you and I both agree that, I mean, I think the damage, the accumulation of damage, intracellular, so inside the cell, outside of cells, on cell membranes, proteins, DNA, on and on. I mean, I think that is a driver of aging and essentially causes aging. I would say it is aging. Yeah. And I focus more on the, an easier solution, which is the nutritional aspects of preventing or allowing your body to, you know, metabolize and produce energy the best it can. And even though you're still going to age, like even if you're at the optimal amount, I mean, even if you have the optimum amount of, you know, micronutrients, you have these minerals and vitamins. that are essential to run your metabolism, they're essential to run enzymes that repair damage,

you know, so on. The fact is you will still age. The question is, you know, how much better by the age? Yeah, exactly. The question is how much better? And I'm all for all of that work, you know, a lifetime, why Bruce and I became friends a long time ago was because I absolutely endorse the idea that we need to do the best we can for the population to get them to an average level of nutrition. But I think the critical thing to understand is average. If you ask about the difference in terms of health expectancy and life expectancy between, let's say, the middle 10% of the population and the bottom 10% it's a large difference. And that's the difference that we're talking about here, the difference that Bruce has tried to do something

about by making sure that if the poor won't eat fruit, then that we fail a multivitamin and so on. But if you look at the opposite end of the spectrum, if you look at the difference between the middle 10% and the top 10% in terms of health expectancy and life expectancy, it's basically nil. Of course, I'm factoring out genetics here. I'm talking about lifestyle. I'm talking about things that we can modify. And that's really important to remember because it's so easy from the popular press and so on to get the impression that if you just do what your mother told you do and do it really well, you know, you eat a really good diet and you get a lot of exercise and you never drink anything and you never smoke and so on,

then you're actually going to live 20 years like that. longer than you otherwise would. When in fact, the message of all of the data we have, epithelological or anything, is that it's probably closer to two years, if that. You know, I mean, the example I like to give is just a very simple one, looking at national life expectancies. So people laugh at the USA a great deal because of the fact that it sits at number something like 45 in the league table of longevity among the industrialized world, despite the

fact that you guys spend far more per head on medical care than anybody else. But if you look at the absolute numbers and you look at the actual difference in number of years in life expectancy between the USA and the number one big country, namely Japan, it's only four years, only four years. Yeah, no, I'm familiar with this data. It's five years, actually. The average lifespan expecting the United States is 79. In Japan, it's 84.

And what's really interesting, so first of all, I'm not sure that Japan has the optimal diet, you know, in general, they're getting all the micronutrients. I mean, you know, there's a lot of factors here. But what I do find interesting is if you look at the data, so right now, the average difference is five years. And in between males, it's four years, between females is six years. If you look at the data from 2012, 2013, Japan has gone down in their life expectancy. So their average life expectancy has gone down by a year, a year, US has gone down by year. So there was a bigger difference. It was six years. But what's really interesting is that the male life expectancy in Japan has gone down by four years,

almost four years, three points. Okay, so these are the kinds of fluctuation in data that I find very untrustworthy. Yeah. I mean, I think that, you know, it's possible that, you know, Japan's becoming more westernized, males also smoke like chimneys over there. So, I mean, there's a lot of other factors that, you know, come into play. Could be that. Could be quality of data, you know. Could be quality of data. data, exactly. I think that if, like you mentioned earlier, you know, if you really want to look at the effect of diet on lifestyle, then, you know, looking at obesity, you know, obesity is associated with a seven-year reduction lifespan.

Yeah. More of it obesity is associated with 14-year reduction. Oh, don't get me wrong, of course, but that's the low end versus middle that I was talking about. But it's growing problem in the United States. You know, obesity is... Well aware of that. Gileshansky, of course, has been very prominent. in publicizing this problem and predicting that unless we do something very serious about the obesity epidemic than we are in danger of seeing a fall in the life expectancy in the USA. But of course we haven't seen that yet because the problem is too new. It's what?

The problem is too new. Too new. Yeah. So I do think that, you know, I talk a lot about what role micronutrients have in diet and metabolism. I mean B vitamins are run your mitochondria, magnesium is needed for DNA. par enzymes, vitamin K is needed to blood clotly, on and on. So, you know, it's also plays a very important role.

And I do think it absolutely affects the way you age, especially if you're talking about living in an unhealthy, eating refined carbohydrate sort of diet versus eating your greens and exercise and things like that. But even with that said, in doing all those things, you're still going to age because you can't stop the breathing in oxygen and eating food, this process that, you know, is coupled together to make energy, well, it's inherently makes damage. Yeah. And there's no stopping it, no matter, I mean, no matter what amount of nutrients to get.

Which of course is exactly where I came in, back in 2000, with the realization that even though we couldn't stop this damage from being created, we could go in and comprehensively, not necessarily 100%, but very, very comprehensively repair that damage and thereby keep its overall level of abundance to a level that the body is set up to tolerate with full funding. So with these discoveries, CRISPR technology, you know, pluripotent stem cells. These are huge things. Is this advancing your research? Absolutely, absolutely.

It's advancing our research just as it's advancing everybody else's. These are techniques, technological innovations that, just like the fact that we can now have the sequence of the human genome, they just make things easier and faster. CRISPR, I would single out as a particularly important advance because there are definitely quite a few things we're going to have to do in getting this damage repair to be comprehensive that involve genetic modifications. And some of those genetic modifications are going to be possible to do ex-vivo in stem cells that we then re-inject into the same person.

Some of them are not. Some of them are just going to have to be done by bona fide somatic gene therapy. And as we know, somatic gene therapy has had a rocky ride over the past 20 years. or ideas because it's really difficult to make it safe. And the fundamental reason it's so difficult to make it safe is because the viruses, the vectors that are used to get engineered DNA into places are not easy to control in terms of where they insert themselves into the DNA and thereby they are not easy to control in terms of what damage they may do, making itself cancerous, etc.

CRISPR on the other hand started out being pretty good at the site's specificity and better than that, as time's gone on, very rapid advances have been made such that now it's just other site-site specific. It's incredibly high fidelity. That means that one can increase the tighter, the amount of engineered DNA that you stick into the body that's supposed to go and modify cells, and by increasing the tighter you can increase the penetrance, the proportion of cells that are actually modified in the way you want without increasing the off-target effect because the off-target effect has been eliminated by the nature of CRISPR.

Yeah, I think that using CRISPR, I think there's obviously a lot of things that need to be overcome, like getting it to the right tissues. I mean, you still have to have some sort of targeting sequence to say, okay, we want CRISPR. It's easier to do ex-viva when you take your blood cells. XVo is always going to be easier. Right. But saying, you know, we want to get this to the liver or we want to get this to the heart. Or muscle, yeah, that's right.

Yeah, that's right. Yeah, much more difficult. And, you know, that there's some of these technologies that you were describing about, you know, engineering cells to have certain viruses that, you know, make them go somewhere or change a gene. Also, we don't know what their effects are in terms of putting them in our body. Are they going to, you know, cause cancer? I see sort of the same challenges with the induced pluripotent stem cells.

So being able to make a tissue, for example, take a skin cell. from your body and give it the right genetic combination to trick it and reprogram it into becoming a stem cell, a pluripotent stem cell so that it can form any cell in the body. That also takes some viruses at this point, I think. So well, first of all, no, there are plenty of ways now that have been perfected that induce pluripotency without actually using viruses at all. The most recent one that got a lot of attention only a month or two ago was when Helen Blaz group at Stanford showed that they could do it with Messenger RNA.

But it's also been done just by, you know, electroperating proteins in. Of course, the problem here is that the actual efficiency is rather low in many cases, but that's improving. The other thing is the quality of the reprogramming. So the original local Yemen-Narca factors, they work pretty well. But Jean-March-Lemester in France a few years ago, you know, show that if you use six factors, then you can get a much more high fidelity reprogramming. You can even reprograms the essence cells, which you couldn't do with the regular Yamanaka

factors, and so on. These things are, you know, it's enormous field and it's progressing really fast simply because it can. And I'm overjoyed. You know, it's going to make a lot of things easier. That's really exciting. Are you familiar with the fact that placenta is a good horse of pluripone stem cells? It doesn't surprise me in the slightest.

Yeah. And that's just being trashed, you know, every day. But the point is, of course, you know, we want to treat people who are already in middle age, right? So they don't have their placentives any more than they have their umbilical cord or whatever. And if we can do the reprogramming well, then that's fine. Well, if you have enough placenta being banked sort of like blood, then you can potentially find a match. Oh, well, of course, now we're talking about falling short of true autologous administration. As far as I'm concerned, you know, yes, it's good to have matches that cut out.

some of the immune reaction response because of MHC compatibility. But the fact is the real Mackay is taking cells from the prospective recipient, reprograming them doing whatever you want and putting them back into the same person. And the only reason that that at the moment is not what everyone's looking at is because it costs a lot of money to do that on a personalized basis. But as time goes on and we get better and better at these things, that cost is going to reduce. And all this banking stuff is going to be obsolete. Do you know if the reprogramming of a skin cell into, say, a pluripone stem cell, do you know if it's been shown that, you know, everything gets reprogrammed, the epigenetics?

I mean, because you're essentially talking about, you know, if you take it from an adult who's 50 years old to 50-year-old skin cell, I mean. So this is what I was saying, well, this relates to what I was saying in a moment to go about using the original Yamanarcha technique versus refinements of it. So for sure, it's been shown by a number of groups that the standard, methods of creating induced pluripotent stem cells do not 100% erase the epigenetic state that the cell came from. There is a retention of some epigenetic memory, as people are calling it. That epigenetic memory is considerably less in this system where you use six factors that I mentioned, and of course other people are looking at other ways to eliminate it even

further. Then again, of course, you've got to ask how much elimination is needed for a particular purpose. Isn't it, is it in fact fine for cells that started out? being skin but you're going to use them for blood to actually have a little bit of skin behavior in them you know does it actually matter you know these are the questions that people are asking all the time all over the world right now yeah well I'm less worried about that and more worried about the fact that you may now have certain genes that should be high more highly expressed at a younger age to make

it younger not so for example you know the the cell cycle regulator ARF P-16 in 4a during early youth early development as we're younger it's silenced, epigenically silence, and that's the reason for that is because if it's not silenced, stem cells stop dividing. It essentially says stop. And so, you know, you want stem cell to divide. So there's two answers to that. The first answer is that, you know, this is reprogramming, right? So if you're raising the whole of the epigenetic state of a cell and taking it back to how it was in the embryo, then you're going to re-differentiate it in the direction you want to the extent that you want, and that's going to make it into less,

say an oligopotent skin stem cell, with its P16 suppressed the way a regular oligopotent stem cell would be and the way that you make sure that's true is just by knowing what to do in the re-differentiation process. So my friend and colleague Mike West at Biotime has been working on this for a while and that's the main thing that Biotime is really good at, this method that controls and systematizes the re-differentiation process. The other thing to mention though is that yes, if you take a bunch of skin cells from an older person, then there's going to be a spectrum of level of expression of, let's say, P-16. Now, it may be that the process of de-differentiation, getting it back to the IPS state

in the first place, is actually going to be affected by that, such that the cells that actually give rise to your IPS cells will be preferentially the ones that happen to have low P-16 in the sample that you took from the original person. So, you know, so what, really? Yeah. So you had brought up this idea a little earlier of kind of, at least I think it's somewhat of an antagonistic pleotropy. When you're talking about, for example, the immune system, you know, it's sort of, you want an active immune system because you want to survive, you know, through reproduction, you want to not die from, you know, some bad, nasty infection.

But also this inflammatory process as you get older can, you know, accelerate aging. Yeah, so you've got to be very careful with antagonistic pliotropy. It's a go of overused term. I'm not even sure that one should call the inflammatory response an example of antagonistic pliotropy. Because remember the situation in an older individual includes the fact that the rest of the immune system has declined. So you kind of need a high inflammatory response just to fight off infections.

And maybe it's a good trade off even in the elderly, irrespective of the fact that it was a different trade off earlier on life. Yeah, I think that's less of an example, more of a better example would be something like growth hormone or IGF1. which is very important for development, for growth. It causes muscles to repair damage. It actually grows new neurons. I mean, it's a great growth factor.

But as you get older and you have more cells that have accumulated damage, that have more damaged DNA, you know, having too much IGF-1 around allows these cells instead of to die, you know, grow. So actually, I would say that that's an example rather similar to the inflammatory one, in the sense that rather than being strictly speaking, antagonistic pliotropy, good in the young, banning the old, this is the case where it's good in the old and banning the old in different ways. So you want more growth hormone in order to have better muscle, you want less growth hormone in order to have less cancer. Right.

And IGF1 also suppresses a transcription factor FOXO3. Yeah, but details of how it works are really relevant. No, but it's, so it's kind of a trade-off, I guess, so maybe less of, you know, this antagonistic pleiotropy. Most of aging ultimately comes down to a trade-off between cancer on the one hand and everything else on the other hand. Right, yeah. So, okay, well, this is all extremely interesting. So is there anything else that we haven't covered? I think we've got quite a lot. Okay, awesome. So if people want to find out more about the S-R-R-R-R-S-R-R-S-R-E-S-R-E-N-E-E-N-E-E-E-N-E-E-A-N-E-E-N-E-E-A-N-E-N-E-E-E-N-E-E-N-E-E-E-N-E. There's two things. Obviously, we have a website. Obviously we have a website, sense.org, S for sugar, E for elephant, N for November, S for sugar, no E at the end, just Sense, S-E-N-S.

Second thing is we have a conference coming up on August the 19th through 21st in Berlin game just near SFO airport and registration is still open. We would be delighted to see people there. It's going to be an awesome event like it was last year. We will have a lot of academic participation of course and also a lot of industry participation. That's very important to emphasize because really our mission is to create a rejuvenation biotechnology industry. And we'll also have people from policy areas and regulatory areas and of course many, many people from the general public. So yeah, it's going to be an

awesome event covering all the bases in this whole space.