Mechanisms of aging and longevity (1)
ECHO OF MOSCOW and Skolkovo Institute of Science and Technology SKOLTECH present the International scientific and educational media project "Conversations for Life".
M. Astvatsaturyan – Hello, dear listeners, viewers, Marina Astvatsaturyan is at the microphone, Natalia Yakusheva is a sound engineer in the studio, this is the premiere issue of our series "Conversations for Life", it is dedicated to the mechanisms of aging and longevity. And we have a world-famous researcher of aging processes, professor at Harvard School of Medicine and a member of the American Academy of Sciences Vadim Gladyshev. Hello, Vadim.
V. Gladyshev – Hello, Marina.
M. Astvatsaturyan – I am very glad to see you.
V. Gladyshev – Yes, I am also pleased.
Vadim Gladyshev is one of the most cited scientists in his field, the field of research on the mechanisms of aging. And he is also one of the most successful Russian scientists outside of Russia. Therefore, until we have started the main topic of our conversation, it seems to me important and interesting for our listeners and viewers to learn about what your path in science was, it is still on the rise, it continues. Well, dotted, at least, mark the trajectory from the beginning to this day. Where did he start this way?
V. Gladyshev – Good. Well, I grew up in Orenburg, graduated from school No. 10 there... and when you like some subjects, you start participating in Olympiads, I participated in chemical Olympiads, won there a couple of times at the regional one. We had a wonderful chemistry teacher, Maria Georgievna Koshkareva, and we had such a... well, we could say a chemical club, where we came after lessons, did some experiments, solved puzzles, and our school was ordinary, but we went to the Olympiad, say regional, and could take all the first places. Then I graduated from school, well, how would it turn out that I know chemistry best, where to enroll? I went to Moscow State University.
M. Astvatsaturyan – To the chemical faculty?
V. Gladyshev – To the chemical faculty, yes. I entered the chemical faculty of Moscow State University, graduated from Moscow State University, well, again, the standard way to graduate school. I graduated from graduate school there, and came… The Soviet Union just collapsed. And the question arose: what to do? From my course, probably one third of people went abroad to study science, one third probably went into business, many are now successful businessmen, even there is, in my opinion, one billionaire. And some of them became engaged in science in Russia. Well, it turned out that I... how would it turn out that I went to America.
M. Astvatsaturyan – What year was it?
V. Gladyshev – It was the 91st year. I just defended my PhD thesis, and in this regard it was… Well, you can say successfully in the sense that it was easier to leave. If we say, well, I would have been younger, then there were still difficult years ahead, if I had been older, then people would have already sort of decided…
M. Astvatsaturyan – The seats are already occupied, yes.
V. Gladyshev – Really, I didn't actually work in Russia, that is, I... well, that is, I defended myself, right? And went to work in Washington.
M. Astvatsaturyan – When did you get to Harvard?
Washington is Bethesda, I guess?
V. Gladyshev – Yes, yes, these are the National Institutes of Health. I submitted several applications and now I was offered to come there. And it turned out to be a very strong laboratory, a lot of academicians, future Nobel laureates worked in this laboratory in previous years, and well-known leaders were there. In general, there were a lot of stories there too, it was a biochemistry laboratory. So I worked there for a few years, and then I got a professorship at the University of Nebraska.
M. Astvatsaturyan – Oh!
V. Gladyshev – In the city of Lincoln. And I worked there for 11 years. And then I was offered to move to Harvard, I moved the laboratory, and since then there.
M. Astvatsaturyan – That is, right now with the laboratory.
V. Gladyshev – Yes, he moved the whole laboratory.
M. Astvatsaturyan – Has your family been traveling with you all this time? By the way, where did you form a family, in Russia or in America?
V. Gladyshev – Well, the family was formed in Russia, but already the children were born in America.
That is, two were born in Washington, and the youngest daughter was born in Nebraska.
M. Astvatsaturyan – And now a laboratory at Harvard.
V. Gladyshev – Yes, yes, yes, it goes on like this. We do science, yes.
M. Astvatsaturyan – And new publications of this laboratory appear all the time. Well, let's turn to our topic, after all, what is aging? What do I mean: is it a program of the body, or is it the wear and tear of the system, is it a pathological process, or is it a physiological process? That's what you think?
V. Gladyshev – Well, in our area this is such a difficult question. How would it sound strange that people are engaged in aging, and…
M. Astvatsaturyan – They don't know what aging is.
V. Gladyshev – They don't know what aging is, yes. Well, here I will give an example to explain. There was a conference before the pandemic, well, a year and a half ago somewhere in Canada. Just by aging. And so it turned out that the organizers gave a questionnaire to the people who came, where it was necessary to define what aging is, when it begins, how best to influence it. And it turned out that the answers were completely different. People understand this in completely different ways, as it turned out. So, and it was somehow even a little unexpected in our field, because when we see a person getting old, we see it, that's… Well, that's it, or the car is getting old…
M. Astvatsaturyan – There are visible signs.
V. Gladyshev – Visible signs, yes. It's like we understand, and it's such a very simple process. Well, we face this on a daily basis. But when we try to determine what its main essence is, it turns out that people see it differently, and even scientists. Someone believes that aging is an increase in the likelihood of dying with age. Well, indeed, in the human population, the probability of dying doubles every 8 years. Well, let's say at 60 a person is 2 times more likely to die next year than at 52. And twice as likely as 68. This is one group of people who think so. The second group of people believes that aging is a loss of function with age. Well, a person thinks worse, I don't know, runs slower, sees worse. This is a loss of functions. And someone thinks that this is the accumulation of damage with age. That is, some side effects of metabolism accumulate, some other harmful consequences of vital activity. And someone thinks that it's just like an aging process. That's how they give a general definition. And it turns out that all these processes, they are interconnected, well, it's obvious that we see all this when we see, say, when a person gets old. But there must be some basic, most important process that determines all the others. And that's what this process is? There is no consensus on this in our area. I am a supporter of the idea that aging is determined precisely by the accumulation of damage with age. What I said here is one of the ideas. And well, why do I think so? For example, if we look at the increase in mortality with age, then we have obvious contradictions. Well, for example, in a person after, say, 30 years, it really grows with age. But if you look at it at a younger age, then there is a very complex addiction. For example, when a person is born, in principle, the mortality rate is quite high. Then it gradually falls…
M. Astvatsaturyan – By the age of nine, isn't it?
V. Gladyshev – By the age of nine, yes. Nine years is a minimum, and then it gradually begins to grow. Here, and there is also some strange period in the region of 20 years, mainly in men. Well, apparently, this is due to risky behavior. And that's why there, from 20 to 25 years, the probability of dying does not increase, it seems to be more or less on such a plateau in men. Well, in general, it doesn't seem to fit the idea. That is, if we believe that the probability of death is what determines aging, then I usually ask this question to my colleagues: well, let's take a child who is 1 year old and a child who is 5 years old. Which of them is older?
M. Astvatsaturyan – Obviously.
V. Gladyshev – Here, and there are three answers. I once made a report – I even remember at the Faculty of Systems Biology at Harvard – and there the professor sits in the front row, he says: well, it's over, it's clear who… Who is more likely to die? A one-year-old, so he's older. I say, well, it doesn't make sense, right…
M. Astvatsaturyan is a paradox, right?
V. Gladyshev – From one year to five, is he getting younger with age? He says well, on mortality – yes. This is aging, mortality, so he is getting younger. Well, other people say that we can't say anything at all about aging before the age of 20. Well, they just say, let's not consider it, and that's it. I think this is wrong. I believe that the body, it ages even at this age, just mortality – it does not determine it at this age.
M. Astvatsaturyan – I really like your metaphor about the fact that life is a river that flows from the mountains into the ocean. Right, right?
V. Gladyshev – Yes.
M. Astvatsaturyan – Under the influence of gravity. It's such a metaphor for life, right? Life is like a river, but the forces of attraction, then the actual process…
V. Gladyshev is aging, yes.
M. Astvatsaturyan – You once said in one of our interviews that aging is the accumulation of damage, and you have said this now. They said that the damage is diluted.
V. Gladyshev – Yes.
M. Astvatsaturyan – How does this happen? And then I will ask you about your theory, because Vadim Gladyshev, he is the author of the deleteriome theory, this is a quoted theory. Actually deleteriom is the amount of damage, but you will tell about it yourself, in support of your theory, right?
V. Gladyshev – Well, the idea is that let's say I'll take one cell, because a cell is actually such a unit of life, right? And when a cell lives, it accumulates damage, well, produces damage. And of course, the cell has a lot of protective systems, when you can spit out some damage from the cell, or grind them, as it were. There are also many protective mechanisms. But it is impossible to imagine that all the damage could be detected. Well, for example, let's say there is some kind of chemical reaction, and it goes almost perfectly, but a little bit not perfect. Well, because there is nothing perfect in biology. And she produced some kind of damage, some one molecule of something wrong.
M. Astvatsaturyan – Has something else gone somewhere?
V. Gladyshev – Yes. And there is no way for the cell to understand that this molecule is there. Because there will be a lot of such molecules, and from the point of view of evolution, it is impossible to imagine a system that will simply be some kind of sensor so that it detects this molecule. And there will be many such situations, respectively, gradually this cell will accumulate damage. And how to dilute these damages, in principle, can be imagined. It's not a problem. That is, if the rate of accumulation of these damages is no greater than the rate of cell division when they are diluted, then in principle, such a form of life can exist.
M. Astvatsaturyan – That is, when dividing, there are fewer injuries than there were in the first parent cell, right?
V. Gladyshev – Well, yes. And apparently, this is such a problem, accumulation, damage in cells, probably existed from the very rebirth of life. From such, the first protocells, when there were no actual cells yet, but just some kind of membrane membrane, and maybe there were some RNA structures there, then the damage was already accumulating, and therefore the cells had to divide in order to dilute these damages. And this is probably the basis of life. That is, if there is a situation when the cell does not divide, then it will inevitably age. And this is what we see, for example, in a person. We have cells that are, well, non-renewable.
M. Astvatsaturyan – Neurons?
V. Gladyshev – Neurons, for example there, cardiomyocytes, some eye cells. Well, there are many situations with the existence of such cells. And accordingly, if there are such cells, then there is such an evolutionary strategy that this organism will age. That is, in the case of a person, this is so. And this suggests that it will probably be very difficult to completely cancel aging. That is, it is generally unclear how to do this. That is, maybe we'll talk about rejuvenation if we have time, probably, but…
M. Astvatsaturyan – Yes, I would like to, in the second part of our conversation.
V. Gladyshev – But nevertheless, if there are cells that do not divide, and which cannot be replaced, and even not only cells, but the structure, skeleton, for example, some elements of the eye again, and so on, then aging, apparently, cannot be stopped in such an organism. And, unfortunately, here is a person, this is such an organism. But there are other organisms that don't age.
M. Astvatsaturyan – I just wanted to ask, what models are used to study the aging processes in general? I know in particular that your group sequenced, that is, read, the genome of a naked digger. A naked digger is an interesting animal, I recently described it to my granddaughter. This is such a naked mouse, that is, a creature the size of a mouse, but without fur, wrinkled like a sharpey, but only very small and with terrible teeth. Just menacing incisors, although scientists who study naked diggers love them very much.
V. Gladyshev – Yes.
M. Astvatsaturyan – I would also like to hear how they squeal, they have some kind of specific squeal…
So you read the genome of a naked digger and what did you see in it?
V. Gladyshev – Well, firstly, he is called a naked digger, he is certainly not naked, and not a digger.
M. Astvatsaturyan – Well, he lives underground, digs holes with his teeth.
V. Gladyshev – Well, yes. He has no fur, but there are such analogs of whiskers, like a cat, only spread throughout the body, they feel them… When they walk in their tunnels, they seem to feel the location.
M. Astvatsaturyan – Do they mostly live in Africa?
V. Gladyshev – They live underground in Africa, and they are very gentle animals. That is, they may seem scary to people, with big teeth, in fact they are very gentle, they will never bite, you can take them on your hand, and they will sit there quietly. An interesting feature of him is that he lives for a very long time, this is the longest-lived rodent.
M. Astvatsaturyan – Does he live very long for a rodent?
V. Gladyshev – He lives exactly more than 30 years. Now the record, in my opinion, is 35 years old, and this animal, which is 35 years old, is still alive. That is, in principle, we do not yet know the maximum life expectancy, but due to the fact that this is a very small animal the size of a mouse, and it turns out to live 10 times longer, longer than an ordinary mouse, this is an amazing phenomenon.
M. Astvatsaturyan – And rarely suffer from cancer.
V. Gladyshev – Yes, yes.
M. Astvatsaturyan – This is also important.
V. Gladyshev – At the same time, cancer also rarely occurs in them. We are trying to understand why they live for a long time. That is, we are, as it were, studying such an experiment of nature. That is, nature has made them live for a long time. And we are trying to understand what has changed in this organism relative to others, and what made it so long-lived. But what we see is some adaptations in the digger that are unique to this organism.
But if we take some other organism... well, for example, we have also sequenced the genome of Brandt's moth, this is…
M. Astvatsaturyan is a bat.
V. Gladyshev is a bat, yes. She is also amazing, because this animal is even smaller than a digger, and lives for more than 40 years. And she had some other adaptations. And if we take, for example, a bowhead whale that has lived for more than 200 years, it has some other adaptations. And it turns out that there are two ways to increase life expectancy. One way may be unique for different animals, but there are some general patterns that we are also trying to understand. And just the general patterns may be even better in some ways, because we can apply them further, including to humans.
M. Astvatsaturyan – Well, it's not just one thing.
V. Gladyshev – Usually it's not one, usually it's like a lot of genes, a lot of some changes in the genome that are involved in this. It's not something, it's just one gene that we took, expressed, and that's it, and it lives 10 times longer there.
M. Astvatsaturyan – And received eternal life, yes.
V. Gladyshev – Yes, no, there is probably no such thing, well, definitely not, I would say.
M. Astvatsaturyan – Please explain, there is such a thing as age-dependent diseases, chronic diseases. Let's designate them for a person. We are talking about aging processes, about longevity, that's what age-dependent diseases are, in relation to a person, not to a naked digger?
V. Gladyshev – Well, age-dependent diseases are some kind of chronic diseases, the probability of which increases with age. Well, the most typical examples are cancer and diabetes.
M. Astvatsaturyan – That is, cancer is still a probabilistic thing, by and large.
V. Gladyshev – Yes, yes, yes, he... the probability of getting cancer is approximately similar to the probability of dying. That is, on average, cancer approximately doubles every 8 years. But it's a little different for different cancers, naturally. Some cancers, for example, are often found in young people, but these are rare cancers usually in the population. And in general, yes, the probability increases with age…
M. Astvatsaturyan – There was even such a popular idea that sooner or later everyone will live to his cancer if he does not die.
V. Gladyshev – Well, not everyone, yes, but there may be 20%.
M. Astvatsaturyan – 20%. It's cancer, and what else?
V. Gladyshev – Heart disease, well diabetes… There are many of them, almost most of the diseases that we know about are chronic diseases that occur in old people. These are age-dependent diseases. And they are usually studied as diseases, diabetes, for example. But in fact, age is the main risk factor for these diseases. Actually, that's why we are working in our field, because we are trying to understand what aging is and how to influence it. Because if we could influence it and slow it down a little bit, just a little bit, we could push back the age when these age-dependent diseases will arise. Probably, they will arise anyway, or maybe, if we defeat them, some others will arise, unfortunately…
M. Astvatsaturyan – I also wanted to ask you more about the effects on aging, because I know that you are conducting experiments, but we will leave this for the second part.
V. Gladyshev – Come on.
M. Astvatsaturyan – And now, to finish, I will ask about something else ... I understand that it will not be possible to answer this briefly, there are different opinions, please give the main ones: when, where does aging begin? There is also no consensus among experts here?
V. Gladyshev – Well, this is just a very big topic. Let me tell you this: we just published an article, literally a month ago. And you probably don't even know about it yet.
M. Astvatsaturyan – No, I don't know.
V. Gladyshev – In it we defined how we count the beginning of aging, the period of the beginning of aging.
M. Astvatsaturyan – Please tell us.
V. Gladyshev – Yes. Well, maybe I'll tell you a little more, so that it would be clear how such a question arose in general. So, in the XIX century, such was the scientist August Weisman. And he proposed the idea that the body can be divided into the so-called soma and the germ line. Here is the germ line – these are spermatozoa and oocytes, that is, gametes, from which a zygote will then turn out when fertilization occurs. And soma is everything else. It's something that's kind of mortal. And he says, here's soma, she's mortal, and the germ line, she's immortal, she doesn't age. Well, it really makes sense that she doesn't age, because if she were a little older at the end of life, then how would the next generation start life at an older age. It would be older, and the next one would be even older. And then the entire population would have died out at some point.
But this does not happen, which means that the initial age in each generation is the same, some very low.
M. Astvatsaturyan – Yes.
V. Gladyshev – Well, on the one hand, it makes sense.
M. Astvatsaturyan – Well, this is a logical construction, in general.
V. Gladyshev – Logical. But then, if we take, for example, oocytes, how can we imagine that they do not age? These are living cells, so they produce some kind of by-products, right? They have some mutations accumulating, they have epimutations accumulating, some metabolites are produced there, some proteins, they have modifications. That is, obviously, they should age. And then it turns out a contradiction, of course, this germ line here – it should also age. And then, when an egg is fertilized, then its age should be older, right?
M. Astvatsaturyan – Well, yes.
V. Gladyshev – How then is it? And then we assumed that there could be such a situation that, say, the germ line is aging, but it is rejuvenated already in the embryo. That is, after fertilization occurred, but not immediately, but gradually. That was the idea. I published my first paper earlier this year when I proposed this hypothesis.
M. Astvatsaturyan – Is this a theoretical work?
V. Gladyshev – Theoretical, yes. But now we have an experimental article, as I said a month ago, in which we just…
M. Astvatsaturyan – Where did you come out, excuse me?
V. Gladyshev – She is in such a journal, called Science Advances.
M. Astvatsaturyan – Yes, there is…
V. Gladyshev is a fairly good magazine. So, we began to determine the biological age during embryogenesis. And it turned out that it falls first from the fertilized egg to the stage called gastrulation. When, let's say, there is the emergence of three main types of cells, inside the embryo. Just such a mixture of identical cells, and then there are…
M. Astvatsaturyan – Three germ leaves.
V. Gladyshev – Three different, yes. So, at this moment, approximately at this moment, the lowest biological age of the organism is obtained. And we assume that it is at this moment that the biological aging of the body begins. That is, it turns out that the organism then begins to age, ages, ages, ages, and the germ line ages, and then, when a zygote, an embryo, appears in the next generation, then, as it were, rejuvenation occurs again. And this stage of the lowest biological age, which we call ground zero in English. Like a starting point, or something.
It can correspond not only to the aging of the body, but in some ways to the life of the body. After all, it can be assumed that the life of the organism begins during fertilization, but the fact is that in the beginning what happens? There is one fertilized egg, it begins to divide quickly into identical cells, which are called blastomeres. And if, for example, we take one blastomer, separate it, the same organism will grow out of it. This is how, strictly speaking, these twins or triplets arise. When division occurs. Or, for example, you can take one blastomer from one embryo, and another blastomer from an embryo, connect them together, and then you will also get an organism. That is, there is no identity of the organism, there is, as it were, such cellular life.
Not only can blastomeres be taken from different embryos of the same species, but you can even take them from different species. That is, for example, take, for example, one embryonic cell from a mouse, and one from a rat. Combine them together, and you will get an organism in which approximately 50% of the cells will be mouse cells, and 50 will be rat cells, and such a chimera. And now there are also a lot of such chimeras made on different organisms, not only a mouse and a rat, but also some other combinations of organisms. That is, there is no identity of the organism, so we can say that such an organism's life – it also begins at that moment, at the moment of this ground zero.
M. Astvatsaturyan – Well, here we should ask, of course, what is biological age, and I will ask, but in the second part of our program.
V. Gladyshev – Good.
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