Jan Vijg Interview Transcript

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Bruce McCabe: Anyway, we can just keep talking as we were. But if I just start with you though, just before we get back to aging, I'd like to get a bit of context because, you are professor of genetics. And the chair of the genetics department here at the Albert Einstein College of Medicine. What was the pathway that took you here? Did you have some early catalyst for an interest in research around aging and aging process? Or was it into the genetics first and then you took a turn? How did you get to this point?

Prof. Jan Vijg: Well, it was, I was always interested in history on the one hand and biology, especially molecular biology on the other hand, already since I was a kid actually, or as soon as I began to realize that something like that existed, I guess. But then the history, it was not so easy to study for me because I had a little bit more biological background. I went to a school for technicians first, and you don't have that here because here's only college and universities. But in Holland, you have schools which guide you more specifically to a job. And mine was laboratory work, which I liked.

BM: Okay.

JV: That's why I picked this school, obviously. So it was much easier for me to go to university and study biology, which I did. Then I picked molecular biology because I like that a lot. Especially when decoding DNA came out and that was fascinating. So I like that. Then I was in my final year for my Masters at the time, and then there was somebody from the United States, Roy Walford, he's dead now, but he became well known because he had this, they had this isolated, I forgot the name of it, but it was this isolated place somewhere in Arizona. They were closed off from the rest world thing. You had to feed yourself and grow your own stuff everything, I blank on the name. He was part of that. He became famous, but he also did a lot of research on caloric restriction. But why I was interested in him, he gave that talk and this was about where he pointed out that lifespan was related to DNA repair. That the better your DNA repair quality, the longer you lived. And he made a big impression on me. And then I thought aging is a fascinating topic. So they asked me to do a journal club on that at the time, and I liked it. So I thought I wanna study that. And then I picked my... I could get a... I had a couple offers to work and then the one that, well, there was an aging institute in the Netherlands at the time, and that's where I went.

BM: Interesting.

JV: I liked it, yeah.

BM: And so he was writing about calorific restriction.

JV: Caloric restriction.

BM: Restriction, which has now become quite a popular approach for...

JV: I won't say popular, [laughter] but...

BM: Yeah, it's no fun.

JV: It's a theory of life extension. Yes.

BM: It seems to be one of the few things which is positively correlated with longevity that we can all practice. Is that fair? Yeah.

JV: Well, it is fair in the sense that, when you stay within the species, within mice mostly, but also flies or worms or when you feed them, a low caloric diet, it's a little bit more complicated than that nowadays. But still, yeah if you've... If you eat less, significantly less, it is, say one third or so or what you normally get, something like that. I don't know exactly. Yeah, you live significantly longer, meaning like 30% or so. It's not so easy to say, it's for sure you live longer and certainly healthier, they also try that in monkeys. And the effect in monkeys is certainly less than in mice. Monkeys are longer lived, of course. And it's not even clear if there's actually an extension of lifespan in monkeys. It's certainly, an improvement in healthspan. There's no doubt because monkeys also get, diabetes for example, when they age. And basically, you prevent diabetes when you have a low caloric diet. It's not a real surprise, not. So you will undoubtedly avoid a lot of diseases when you can no longer eat as much as you want to, but you are limited. And that's, I think what caloric restriction is doing, it really does affect disease. It improves your healthspan, so your chances of surviving longer are bigger and bigger and bigger. But again, it's not like, if you can, when you would be a human, you can live until you're 150 or so.

BM: No.

JV: So you probably will, when you would do caloric restriction as a human, which well, I maybe there were a few in the past. I don't know. You may get closer to this limit or 115.

BM: Sure.

JV: But you will not be able to break it.

BM: Yeah.

JV: But again, to...

BM: 115 years, yeah.

JV: It's difficult to have hard evidence for that. And you can imagine why that is, because, of course, the humans live too long, you will not be able to wait so long and to see the actual effect of that. And apart from the fact that nobody likes caloric restriction, not, but in mice we can do it. But again, mice, first of all, most of the mice we are working with are mouse strange. They're inbred, that they're not really the same, they're not really good models for humans. And also because they are different strains, they have their own peculiar disease patterns, and they can eat as much as they want to. And they don't really live under optimal conditions. Not we think so because they're in a cage. They have... They don't get cold. And they have food as much as they want to, but it doesn't mean that this is their optimal condition.

BM: Yeah, of course.

JV: So we don't really know how long a mouse can live. The best way to do that would be to study a million mice in their own natural environment, but now make sure that the temperature that they have, shelter so that the temperature is not an issue. because in the wild, mice die from cold very often, that they have food enough. Because in the wild, my style from hunger quite often, and there's no predation because in the wild mice are being caught. [chuckle] So, yeah if you would do that and still let them live in optimal condition, then you would probably know how much a mouse really can live maximally. If you don't know that, and that's why it's so difficult, because when you have a group of, let's say, 50 mice and you do caloric restriction on another group of 50 to compare them, then yeah in the caloric restriction group, which is much healthier, there will be more survivors, not. So they always say, well, maximum lifespan is increasing, but it's a little bit of fake because there is no evidence that caloric restriction increases the lifespan of a species. Yeah. So in other words, let's assume we would know the normal lifespan of a mouse. And suppose the mouse limit would be, let's say three years. It's probably a little bit more, but it doesn't matter. Well, caloric restriction now bring that limit up to four years? No, it does not. I think that's very... There's absolutely no evidence that it does.

BM: So the last five, maybe 10 years now, there's been this upwelling of interest and excitement around the potential for rejuvenation, which I'd like to get onto in a minute, but I guess the Yamanaka factors are... We discovered these proteins can restore the potency of cells, their ability to divide and all these sorts of good things. And there's some pathways we think or lots of people think and I wanna explore what you think between that discovery and actually being able to expose cells to chemicals or whatever the... To actually do that on a more restorative basis of organ by organ basis or a whole of body basis. But before we even get to that, the mechanisms for aging, as I understand it, we're talking about changes in the DNA breaking... The DNA breakdown, but also in the epigenome. So do we... Are we arriving at any consensus there or is there still multiple strands of thought as to what the basis of aging is?

JV: Yeah, in my mind, you hit the nail on the head. The interest lately... Well, lately the last decades …

BM: Yeah.

JV: … Is really in life extension. Either using caloric restriction as you just described, or mimics of calorific restriction compounds that have been tested in mice like Rapamycin, Metformin, and now of course partial reprogramming or...

BM: Yes.

JV: They call it rejuvenation, but it's not really rejuvenation. So...

BM: Partial reprogramming. Well, we'll use the right terminology. Yeah, yeah.

JV: Yeah. Partial reprogramming, because when you do complete reprogramming, you can turn a normal somatic cell into a Pluripotent Stem Cell. Now that you don't wanna do. So you really want that the cells to stay functional. So you do... They invent. They discovered that this could be... That Murti did actually, from... Where was he in? In California, at least. So he'd... He come up with that for... He was the first to do that. And now there are a couple of others who did it also. But we don't know that much about it. First of all, of course it's... It's a little bit risky to play with cells like that because they can become cancerous, not. But we don't actually know the mechanism behind it. It seems pretty clear that there is a benefit, but this far at least people didn't study this in really old animals to see if you can really extend the lifespan of old animals using that mechanism.

JV: And they usually pick like a model organism, like a mouse with a defect, and it was... It showed what they called premature aging, and they showed that it benefits that mouse or they used the mouse when it was still fairly young. And they called it old at that time, and they showed that it had some benefits. And I believe the benefits. I've seen those papers, they seem very convincing to me, but yeah. I mean, how there's no evidence that you can use that mechanism to make, to break through that limit to a species lifespan and really dramatically increase human lifespan. I don't think there's evidence for that at all at the moment.

BM: Okay.

JV: There is no evidence for that at all at the moment.

BM: Yeah.

JV: But I also think it'll be unlikely that that will work. I mean, to make it clear, I have no doubt at all about the benefits of doing that research, which you call geroscience. Because what you ultimately wanna do of course is to improve health, and you don't want people to be sickly when they are in their early 70s. But you want them to stay healthy until they're in their 90s or longer. So that then yeah in the short time they may still die because at the end we die. But then at least they had a good, healthy, long life. That's what you wanna do, and that's also testable, not… You can test all these things on older people and that's good. That's what you wanna do. And to come up with stories like... Well, we can reprogram ourselves and then we can become 150. I don't think it's very fruitful apart from the fact that I don't believe it's possible that's in that paper, actually.

BM: Yeah. The paper you just handed me In Nature, Why Gilgamesh Failed. Yeah. Okay. So your position is that longevity is fairly fixed as a species and breaking that boundaries is probably not a productive way to think about this. But perhaps a more productive way to think about it is that by understanding how to do partial reprogramming, there might be all kinds of other benefits to fall out of that in terms of therapeutics or...

JV: Exactly. Yeah, yeah. That's certainly the case. I mean, we... And even if not, then I would still think that kind of research is very important because you wanna know, not?

BM: Yeah. Of course.

JV: That's why you decide you're not going to do science because we planned this and this. because science really cannot be planned very well. So you have to do free research and follow your notes to some extent. And that's good. So that's why I'm all for research like that. I only say if somebody like you asked me, "What are the chances that you can really beat aging and live until we are 200 or even 150?" I said, "That chance as a scientist, according to the evidence that I'm aware of, the chances that you will do that is zero. It cannot be done." And the explanation for that is also not that difficult. I mean, this is essentially the evolutionary basis of aging here. I mean, we have not one clear because of aging, but we have many causes.

BM: Can we dig into that a bit? The becauses of aging? because I really wanna understand as in as many...

JV: Yeah.

BM: The layman's terms if possible.

[laughter]

JV: Yeah, yeah.

BM: What you believe are the major mechanisms of aging. because I've read about the epigenome and to me that's just really amazing because when I grew up, everything you learnt was that DNA was what you passed on. And there was no way of passing on heritable traits outside changes in your DNA. But now we've got chemicals bonding to the DNAs. That's kind of how I picture it.

JV: Yeah.

BM: The epigenomic thing over a life based on your environmental exposures. But somewhere in there that mixture that or that all accounts for aging, so.

JV: Yeah, of course, the epigenome became very popular, but that was actually after there were some disappointments in testing the genetic basis, in seeing, well, that was the idea that I'm working all my whole life. So I'm biased that aging can be caused by accumulation of DNA mutations. So changes in the DNA sequence, that's of course causing cancer. So you would say, well, since we already know for a fact that that causes cancer and cancer is very age related, not, you would say...

BM: Yes, it is.

JV: It's only a small step to say, well okay, if it causes cancer, such a major component of aging, then probably it causes aging in general too, no?

BM: Yeah.

JV: But that was very difficult to test. There were no good methods to do that. So my feeling is that then it seemed like easier to study the epigenome. So then they moved that way. But also the epigenome is modifiable. So that sort of makes it all like more attractive in a sense.

BM: And more attractive from a research target because you can ... more manipulatable. Is that what you mean?

JV: More manipulatable. But that actually is also not true because if you really think about it, the epigenome was studied in a way that made the assumption that all cells were more or less the same. So you have a tissue, where you grind it together and you measure the epigenome, but then what you measure is the epigenome exactly as it is in all the cells. But that's unlikely to be a based, a basic mechanism of aging. Because if you would change the epigenome in all cells at the same positions, then that's actually a program, not... That's what cells do collectively.

BM: Yeah. And it's unlikely an environmental exposure.

JV: Yeah.

BM: That's unlikely to, it's more likely to be random and chaotic.

JV: Yeah. Well, it's not, as was pointed out to me fairly recently by somebody, a good friend and colleague, she said, "Well, but you can have like a general loss." For example, you probably know about DNA methylation. You have these methyl groups attached to bases and they, they call it the fifth base because there are only four different bases. But then you add a methyl group to one cytosine, then it's turning itself into another base. So you have fifth, five and you can make a new code out of that. So that's actually what happened. So that's there. But you can, of course imagine that randomly these groups, these methyl groups fall off. So you get, you still get a random process where you lose methylation. But that can also affect the genome overall. And that can be in that sense an effect. But when you measure methylation patterns, you usually do that because they mean something, like you have a particular process that happens actually memory formation, for example.

Memory formation is clearly a process that is part of development. And actually it goes on until aging, not? And that is associated with very specific changes in the epigenome. So the epigenome builds something. And that, of course, is not a random process that is basically the same from cell to cell. A whole bins of neurons, they all have the same changes in the epigenome. But there are many other processes that are developmental in nature, or we call them adaptive. So they are processes that have been selected for by evolution, because they serve a function. Now that's not aging. You see, aging doesn't serve a function. Aging is a random thing. Aging is stochastic as we call.

BM: Death serves a function though, in terms of selection processes in a species.

JV: Well, you can think of it that way, for sure. But I would think the other way, of course I would say, well, evolution selects set of gene variants that provides an advantage into certain conditions and for environmental conditions. That goes at the expense of a whole bunch of subjects.

BM: Yes. I guess it's a more the positive rather than negative.

JV: Yeah. But that's, of course how it work, not because that's how evolution work. That's why there's an enormous diversity of life. Because continuously the ideas in mutations, and now we are sort of talking germline here, but unicellular organisms, they've only one germline. And it's so much the same, not so is unicellular, but they exist 2 billion years longer than multicellular organisms. And whenever there's a mutation, it either is, it has no change or it is bad, and then the cell die, so you lose it and, here, and very rarely there's an advantage in under the current conditions. So now, the cell is growing fast and the offspring all have the same mutation. That's how it works. And at some point, cells group together and, you know, I'm not the one to explain how evolution did that, but that's the great evolutionary biologists...

They know how to explain that kind of thing. And it's always sounded very convincing to me. [laughter] Here you notice something, not, we sort of rely on each other very much. I wouldn't doubt one of my colleagues, one of the experts, when they have good reputation and I've seen many papers and I know they're doing good work, I trust them. So I rely on what they say because their specialty is little too much for me. You cannot be a specialist everywhere. So to a large extent, I adopt those points of view. And that may not always be correct, of course, because they can make mistake. So that's why I'm always careful. I say, well, as far as I know, that's okay. So here also it seemed to me that the basic processes of aging must be some sort of stochastic process that has randomness over it, that is not serving a function. And there are responses to that. And those responses can be programmed. You can easily imagine that inflammation came from hyperactive immune system that was, of course beneficial, not? In early life, it certainly is. But then when you grow older, then there are disadvantages that only show when you're older. And the similar thing is for growth hormones. IGF-1 for example, or growth hormone. There's a benefit to growing strong early on, not, because you...

BM: Definitely.

JV: Can compete with the others and you have a lot of offspring. But then we now know a high level of growth hormone IGF is exactly not so good because if you dampen it down as they did for the first time in little worms, then they live longer. And flies live longer when you do that. And mice live longer when you do that. And humans may also be healthier when they do that in humans. But... So there are many of these mechanisms and that gives you a set of mechanisms of aging that are metabolic in nature. But let's suppose for a second now that there is one basic cause of aging. Let's suppose to make it easier for me because let's suppose there's mutations. Mutations are unavoidable and they're necessary because without it, there wouldn't be life.

BM: Absolutely.

JV: So it's fairly easy to say, Okay, since they occurred anyway, they had bad effects. We know that most of them have bad effects and you die. So you can easily imagine then that that was a fixed cause of aging and it couldn't be avoided except by when in the germline and again, unicellular have only... The germline is the same, Then a particular mutation generated to new improved version of DNA repair. So it could prevent mutations. Never completely. Because you cannot do that because once you do that, you will...

BM: Well, they stop the species.

JV: Exactly. So, but it could adapt. It could say, "Okay, this is a better repair system, now it's more accurate." So the mutation rates is going down so that particular cell can live a longer life."

BM: Yes.

JV: Yeah. That you can sort of extrapolate that to multicellular organisms. The reason why you see that humans probably live much longer than a mouse is because they can protect their genome integrity much longer. However, when that happens, then evolution would do something very nasty. It would realize that you have a particular lifespan. It knows that automatically because then you die, not, that many people begin to die because that's the cause of their death. They know then, well, it doesn't really matter if we create mutations in the germline that make you get all sorts of nasty things at the end of life, because then you're dead anyway, not... So it doesn't matter. So that's a theory, evolutionary theory of aging. I'm not saying anything new here. This is already fairly old. So according to death hypothesis, and everybody's, I believe, convinced that that's actually true, there's a host of variants in your genome that do not do much against you when you're young, on the contrary.

BM: But they sit there dormant until...

JV: Until they... You are so unlucky to actually get older because you are protected in the world, you are normally not protected. Humans never live longer than 25 or 30 years. But now they do. So suddenly, all those nasty variants, they have opportunity to cause havoc in your metabolism. And that's exactly what they do. But that also tells you something else, namely that there's not one single cause of aging.

BM: And you'd never be able to program them out because you could never possibly factor for all those. Well, it'd be so hard to test them experimentally...

JV: That's my point. That's exactly the point I wanted to make. So you cannot develop an endless drug cocktail to target all those things. But even worse, when you would try to do that, there are side effects because a lot of these things are both bad and good. They're good early in life, but they are bad later in life. So when you start...

BM: Maybe start early in life. Yeah.

JV: So you don't wanna do that. So I don't say it's impossible. You should never say things are impossible, but it's going to be very hard to get rid of all these factors and then make us live until 150. But you also probably appreciate how difficult it is to make this kind of predictions. That's why I don't really make them, I...

BM: No. That's exceptionally helpful to me. because it gives you a sense of the scale of the challenge.

JV: Yeah.

BM: And it's actually several orders of magnitude more than I thought.

[laughter]

JV: Well, well...

BM: Because if you're just looking at cellular mechanisms in isolation and all, well, we only have to stop a cell doing function X and keep it doing function Y, but it looks easy. But if you are trying to eliminate all sorts of potential things that might switch on later in life, but you've still going to factor for whether they might be important early in life and you've got to understand all of those relationships and deal with them one by one. That's a huge set of problems to solve.

JV: Well, that's of course why it took evolution so long to do it. Not only long lived species. It took evolution millions and millions of years to create all those variants, genetic variants in the right balance to lead to that longer lifespan. So we have to do it now in one cocktail. And that's sort of difficult.

BM: Good luck. Yeah.

JV: But you can... It's... There's a little bit of... There's some ray of hope here because suppose now that I'm correct and it is really... There's really only one basic molecular cause of aging. Let's again, assume for the moment that it is mutations. Exactly not far-fetched, not because DNA is the primary template. So whenever things go wrong there, you're in trouble immediately. And we know that. So it could easily be the basic mechanism of aging. If that's the case, suppose we have to start there because that's the most difficult. Suppose we can solve it and I was actually just proofreading, correcting actually a new manuscript with a group of people where we try to do exactly that, to come up with new interventions that can slow down mutation accumulation during aging or even eliminate cells with especially high levels of mutations.

BM: Okay.

JV: It all happened because we and others developed new methods to accurately measure the mutations in tissues and organisms. And we now know for a fact that they accumulate exactly as was predicted in the 1950s, they accumulate with age until quite high levels. So we know that. So it's still not to prove of course, that they cause aging, but we are getting there. So that's what we are trying to do there, to come up with this kind of interventions. Suppose we can do that, it's still like blue sky, but let's suppose we can do that in maybe 10 years, maybe 12 years, with 15 years, 20 years, we don't know. But if you can do that then, then you still have all the other causes of aging that evolution gave us. There are all these endless variants, like high cholesterol, high growth hormones and all those things.

But they may be fixable also and that may not be that difficult. It may be that it's really only this molecular basis that is very difficult to fix. And once we know, we understand that what all the other pathways are, we can maybe do it much easier when we can dampen this IGF pathway, for example. There are other coincidental side effects that are also beneficial. People already know that, there are some interactions between them. So theoretically, it may be possible, at least the possibility, in my opinion, cannot be really ruled out that we may be able to first come up with logical interventions to get rid of the basic causes of aging.

BM: Yeah.

JV: We can call it intrinsic causes of aging. The real reason why some species can live until 400 and other species only like a couple of years.

BM: I quite like that verb dampen, instead of reverse or something so bold, is that coming out with mechanisms to dampen certain aspects of aging and then extend the timelines. But let's put aside longevity itself and just get back to some of the spinoff benefits of this kind of research because as it seems, and correct me if I'm wrong, but it seems to me that there's this kind of... There's a spectrum of activity in regenerative health and that where people are targeting organs, they're targeting the macular degeneration sort of issue, diseases. They're targeting individual diseases or individual organs and saying, "Well, we're learning enough to perhaps come up with therapies that can help rejuvenate or restore or slow down, dampen, the aging effect in the optic nerve or in something to do perhaps diabetes", or any of the other things that you might target. Is that a valid way of thinking about where this is going? Do you feel optimism about therapies coming like that out of this sort of a solution?

JV: Well, it's not so much optimism, but I would say the other way around it. I mean, why not? It's certainly a possibility, I would say, but it's also not so easy. For example, the central tenet of geroscience is that it is much better to approach human disease from an aging point of view that clearly is a risk factor for all these diseases. So if you do something against aging, you will be able to slow down.

BM: You'd dampen out all the diseases.

JV: Yeah, exactly. That's the argument. But of course, as you can also imagine people, all these MDs who are studying its individual disease, they are not very happy with that, not...

BM: They don't think that way.

BM: Because, yeah, they sort of get the idea they're out of a job, but they also have a point. Some of them pointed out to me that, look, you're not naive enough to really believe all that, do you? Because they say, Look, yeah, of course, we know that aging is a major risk factor for all these diseases, but it doesn't necessarily mean that when you study your basic process of aging that you can cure diabetes and...

BM: No.

JV: No. And that, of course explains to a large extent why funding for aging is really not that great. If aging would be so important and people would recognize it as so important, then they would spend much more money on it. And go to a typical cancer conference or a typical diabetes conference. These are conferences where you talk about 10,000 people. A typical aging conference, which is supposed to encapsulate all these diseases, There are no more than a thousand.

BM: I think you're on a steep trajectory, though, don't you think? All these spectacular examples like Altos starting off with 3 billion in cash and there seems to be money moving in your direction. That's...

JV: Well...

BM: Quite rapidly.

JV: That's true. That's definitely true. But I really wonder about, we actually mentioned that a little bit there.

BM: In this paper?

JV: Yeah. Yeah, it's certainly true. I'm happy with that. I mean, of course, the more money we get, the better it is.

BM: Of course, yeah.

JV: But I do also think that all that money may be coming because there really are expectations of us living to 150. And I'm afraid that's not a good argument. I think that unfortunately when people would really believe that you can only improve healthspan and never live much longer, they would not donate their money. They do because...

BM: Yeah. There might be a lot disappointment in the... There might be backlash at some point.

JV: Yeah. So I should not complain. That's sort of my point.

BM: Yeah.

JV: Okay, it has been done by claiming that we may be able to live to 150. What's wrong with that? You can make that claim. No, I mean, if people in the past would, when they said, I wanna fly like a bird and I can do it with a machine and everybody said, "Well, you're an idiot. You cannot do that," but we can do it now, not...

BM: Yeah, yeah, yeah.

JV: So it's not bad to do that. I'm happy with Altos. I'm very grateful.

BM: Yeah. At the end day, all they have to do is invent something to address male pattern baldness, for example, and then make billions back.

JV: Well, I would just be happy with that.

BM: Yeah. You and I will both be happy with that. I'm losing mine quite rapidly now. [laughter]

JV: No, no. You're still okay.

BM: Or hearing loss, age-related hearing loss, it's so common. It's so pervasive. If you can just grow those little cilia back and I don't know.

JV: You're absolutely right.

BM: It's huge. Just one therapy like that is massive.

JV: So I actually I'm all for this money. I'm happy they donate it. And yeah, if they silently hope that their lifespan will be increased until 150, that's okay. There's nothing... Yeah. But again, this is science as Friedrich Nietzsche, the philosopher already said in one of his aphorisms. Scientists are really not these dry people who count numbers and because those people, they work in a grocery store. He said scientists are people who basically dream of making gold out of lead. And that is exactly what it is. And if you don't have those dreams, the only thing that unites us or should unite us for sure, that is there's a set of rules developed in the Middle Ages, not...

You can have any imagination you want to, you must, you must have imagination. So of course, it's good to feel that you can become immortal. You can work on something that makes us immortal or that can generate gold out of lead. That's all fine, as long as you do the research and you follow the rules. So you basically follow the rules to test a hypothesis. And if there's clear evidence against it, you have to accept it.

BM: You have to move on.

JV: You have to move on. If you don't do it, then others should correct you and tell you to move on.

BM: Yeah.

JV: I think that's essentially what it is. But that was an invention of the early Middle Ages, the Christian Church. Although of course, people will not recognize it now. They think the church hates science, which the church of course didn't do it, they just created science as we now know it. So yeah. Later the relationship became a little bit bad, but that after... That was after the church already created science. They had already done it, and they instigated the rules for science. So, it's really a misunderstanding. I'm not Christian, I'm not religious at all, but I just...

[laughter]

BM: We digress.

JV: I just know that, it's basically, yeah, we have to basically... We owe them a big thing. And that's not. Yeah.

BM: Well, if we do follow the scientific method as a community, it seems to be a very exciting frontier. It feels like one of those frontiers where we've made a couple of fundamental breakthroughs in yes, the epigenome, and I'm staying that a little bit more, which is I believe, your particular area of contribution has been heavily in that area as well.

JV: The epigenome, you mean?

BM: Yeah. Yeah.

JV: I haven't done that much on the epigenome.

BM: Oh, haven't? Okay.

JV: But I have published papers on the epigenome, especially single cells. Again, that's the argument. I'm especially interested in changes that are random and are different from cell to cell. So that's why you need to study the single cells.

BM: I see.

JV: Yeah. But it's not... There are other ways that epigenome can contribute. So we have to keep an open mind there.

BM: Yeah. So just getting back to the healthspan, where do you think the most, like if you're looking at the research you are reading, that you are doing here, what are the most exciting pathways to follow? For someone like me or for the people I talk to.

JV: No, you mentioned it. I really think also that regeneration now, ways to try to reprogram cells partially that is, I think that is the profitable area now, but we have to be very careful, there are already one for cancer. But, there are other problems as well. For example, when you apply this kind of therapies, you do partial reprogramming, then essentially you do not change anything in that cell. So if it's really true that high burden of somatic mutations, for example, is not a risk, suppose now that we can have 10 times the somatic burden of mutations. If you now measured it, we now know what they are, by the way. We measured it, and in the old days, and maybe 20 years ago, even less people thought we're talking about one mutation per cell.

We now know there are thousand. So it's not little. So you can imagine that yeah, maybe they are not doing a lot and you need maybe 10,000 per cell. Well, we are testing that now. But you can imagine that by reprogramming, you don't change that. So you don't really fix that problem. What you do fix, in my opinion then, it is the only explanation I have, is that in some way you sort of manage cells to turn back to a younger version of themselves, an earlier version of themselves, not a younger version of themselves. An earlier version of themselves that mimics that in a sense. It's not the same, that mimics it. And then it can still, it's more flexible in doing things. So I'm sorry for being so vague, but I think that it's because we don't really know a lot about what's happening. Because as far as I know, at least, there's no explanation for how this partial reprogramming works. The argument would be that it happens because of the epigenome, not, I mean, the epigenome in the event all these isolated changes, and by applying this partial reprogramming, you return all that, and now it's kinda a normal epigenome. Well, I think I would like to see evidence for that. It's very difficult to share that. I don't think there's accurate evidence for that, but it will come in the near future. We'll see.

BM: Are there other messages that you'd like to get out there to people – I speak to a lot of ordinary business people and ordinary people in government – or things you'd like to correct? Are there any things that bother you about the misunderstandings in your field as well, right now?

JV: Well, no. I... You can always argue, of course, that people tend to hype and exaggerate.

BM: They certainly do.

JV: That's certainly true. But is that necessarily always bad? I don't think so. If you don't do these things...

BM: Yeah. If you don't have a dream, if you don't have that big goal.

JV: Right. And also when you do not try to blow up yourself a little bit and your accomplishments, then they will never listen. I remember when I... That was one of the reasons I came to the United States. Because in Europe at the time, and certainly in the Netherlands, you were not supposed to stick your head over the others, they cut it off. because they don't like you to do that. And I think I did it automatically. I did my own research and I came up with new ideas, and I was so enthusiastic and I was presenting it. And then somebody told me, "You sound like an American." And I said, "What the hell?" Yeah. Yeah. I could never get... I was of course a student and students are not supposed to come up with something original.

BM: Interesting.

JV: They have to do what the mentor says. And then, later when they're older, and they get something. But I didn't wanna accept that. And I remember I was in my... At a conference in New York. Was it New York? I was still, of course, working in the Netherlands. And then I had all these new ideas about new methods. And then I... It's a big, very big conference. And then, coincidentally, during coffee break, I was close to one of the organizers and I, of course, talked to them, not... You wanna let them know what you're doing. So I did that. And to my utter surprise, he was interested. And then, he got somebody else there. He's said, "Listen, these guys have something nice to say." And I was talking, I was already surprised. And then he said, "Well, at the end we can put you in the program and give us a short talk."

I thought, "What the hell? They'll do that." Now I did that and I thought it was really very nice of them to do that. And then I wanted to leave after my little talk. And then a woman came up and she said, "Yeah, next month we have a Gordon Conference. Would you like, this is so interesting what you say. Would you wanna come?" And I said, "Look, but this is my conference. I have no money I... " No, no, no. "We pay." "What? They pay me to give a talk." They did. Now that was my total... That was my experience with my first visit to the United States. So I thought, this is the country I wanna live.

BM: It's nice, isn't it? It's one of the most attractive aspects of the United States, that openness and that also can do. They keep... It's not “Why?” but “Why not? Why not?”

JV: Why not? And you can talk and give your opinion and they listen to you. Yeah.

BM: Yeah. That's nice and nice...

JV: Yeah. It's... Yeah. Okay. People can say a lot of bad things about this country, and of course. I do that too. I'm a real US citizen now, so now I can do it. But overall, if you think of the alternatives, then no, I would never wanna live somewhere else. Still for me, this is the country to be. And I'm not a conservative, I'm not a Republican.

BM: No.

JV: I'm a registered Democrat. But nevertheless, I mean...

BM: Well, maybe that's a nice way to bring this to a close. Thank you so much for the time. It's been, enlightening for me because this is an area which is so full of different messages at the moment. It's bubbling over with ...

JV: Good, that's good.

BM: Dialogue.

JV: It's a good sign.

BM: And that's a good sign. But there's also confusion within that, and I think you've helped to give me some frameworks for understanding that...

JV: Great, yeah.

BM: A whole lot better. So...

JV: Email me when you have questions.

BM: I really appreciate that time and I'd like to stay in touch. Thank you so much.

JV: Alright.

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