Mechanisms of aging and longevity (2)

ECHO OF MOSCOW and Skolkovo Institute of Science and Technology SKOLTECH present the International scientific and educational media project "Conversations for Life". The beginning of the conversation is here.

M. Astvatsaturyan – Let me remind you that we are talking about the mechanisms of aging and longevity with Vadim Gladyshev, a professor at Harvard School of Medicine, a member of the American Academy of Sciences, and we continue our conversation with the question of what other theories of aging exist besides Vadim Gladyshev's deleteriome theory. After all, there are six theories of aging, yes, I've heard that each theory makes sense. Can you tell us about your colleagues what they think about aging?

V. Gladyshev – Well, sometimes scientists in our field joke that there are more theories of aging in our field than scientists who study aging processes.

Because on the surface it seems that aging is a simple process, and the people who come to our field are motivated, and they want to figure it out, and they often offer some ideas of their own. All these ideas can probably be grouped somehow, and there are main lines of thought in this area. One direction is theory. It assumes that aging is a programmed process, that it is a program, that there is a need for an organism to live and die in order to free up resources and space for a new generation.

M. Astvatsaturyan – If I am not mistaken, it is Academician Skulachev who thinks so, for example.

V. Gladyshev – Well, yes, for example, he is a supporter of this idea, yes. Well, there are many other scientists as well who think so. This is an interesting idea, because we see that there are such elements of programming. Well, for example, we see that this is the average age of life of an organism of 80 years in a person somewhere now. And somehow organisms age in a similar way, many of them have these diseases, cancer or diabetes, or heart disease. There is a similarity. But from my point of view, this does not mean that the process is programmed. He has an element of programming due to the fact that we have a genetic program of life. This is one such idea, there is also a very popular idea… Well, which one should I call next? Well, let's call it "Expendable catfish", there is such an idea. Her supporter is a scientist Tom Kirkwood, he works in England. And the idea there is that organisms always live in limited resources, resources are always insufficient. And resources have to be spent on reproductive function, this is an energy-consuming process, and also on supporting the body itself. And since there are not enough resources, we have to remove resources from support to the reproductive function, because of this, the support of the body, it is not perfect, not one hundred percent, because of this, it is impossible to remove all the damage, the damage accumulates, the body dies. That's the thought. But it's also strange, because if resources are limited, then part of them should be spent on maintaining the species. There will always not be enough to maintain the parent organism itself, and therefore, this organism will age. One can imagine such a situation that, at least once in some form, there are unlimited resources: here's the food, here's the food — I don't want to, there have been no predators for many generations, nothing dangerous. But we never see a situation when aging suddenly stopped in such organisms.

M. Astvatsaturyan – Well, by the way, I remembered about the idea of reducing calories, is it the most popular, yes, to increase life expectancy? There are experiments on animals where calorie restriction, for example, worms, greatly prolongs life.

V. Gladyshev – But this is rather not a theory, it is a way.

M. Astvatsaturyan – A way.

V. Gladyshev – But this is a slightly different question. That is, there are different ways by which you can increase life expectancy. Here you mentioned in the first part the river, the metaphor of the river.

M. Astvatsaturyan is your metaphor.

V. Gladyshev – Yes. In this metaphor, the force of attraction is like aging, and how long the river flows is the duration, the time of life, and just the time of life can be changed in different ways. But this does not mean that we can stop aging, these are two different issues.

M. Astvatsaturyan – By the way, at the Moscow Conference on Computational Molecular Biology that just took place, your report, if translated from English, was called something like this: "Computing and manipulating the aging process," right?

V. Gladyshev – Yes.

M. Astvatsaturyan – What data did you give there, how can the aging process be manipulated? This is in continuation of the topic that you have touched upon.

V. Gladyshev – Well, the most important thing I said was about methods for determining biological age. Here in our region there has been, one might say, a revolution in the last 10 years. Before that, we could not quantify the biological age. Well, chronologically we know the passport age, but biologically it was difficult to determine. But now new methods have emerged when it became possible, and so I talked about it, how it can be determined, and how it can be applied.

Here you mentioned calorie restriction. If we take mice and limit their calories, actually limit their food and apply methods of analyzing biomarkers of aging, so as to determine biological age, we see that at the same chronological age, mice that eat less, they are younger. Let's say we take a control mouse for 10 months, and a mouse that ate less, she is also 10 months old according to her passport. But really the one who ate less, she is biologically not 10 months old, but 9 months, for example.

M. Astvatsaturyan – This is my key question of the second part: how do you determine biological age? If I come to your laboratory, will you be able to determine my biological age?

V. Gladyshev – We can, yes. We determine by a method called the epigenetic aging clock. Well, for simplicity, we can say this: if we consider DNA, it consists of four types of nucleotides. And one of them, which is called cytosine, it can be methylated.

M. Astvatsaturyan – The so-called methyl groups sit on it.

V. Gladyshev – Methyl groups, yes. And there are millions of such places in the genome, many millions of such places. We can segment the genome and determine with what probability each of these cytosines is methylated. And using machine learning methods, we can find a certain group of such cytosines that form a mathematical model that can predict age. Such epigenetic aging clocks were made on individual tissues, for example, to analyze the aging of the blood, or the aging of the liver, for example, or the brain.

M. Astvatsaturyan – That is, according to these epigenetic labels?

V. Gladyshev – Yes. And out of these millions, a very small number of such labels are selected, because most of these labels — they don't say anything, but some, as it turns out, do. And now there has been such a revolution in our field that it can be determined. It was a bit unexpected. This method was originally invented by a scientist whose name is Steve Horvath, he works in Los Angeles. And a very explosive growth of such research has gone on in our field, a million different watches have been made, and there are a lot of them, thousands of people use them, companies are formed according to the definition of biological age.

M. Astvatsaturyan – I know they have developed an algorithm for dogs.

V. Gladyshev – Well, yes, yes. Now we have an article with him, well, this is his, this Steve's article, but we are co-authors there. And he made clocks on two hundred kinds of animals.

M. Astvatsaturyan – Wow, you!

V. Gladyshev – Yes, that is, it's just some kind of unique work, it hasn't even been published yet, but it's kind of in the process of publication right now. We also use this watch. In my laboratory, the main model organism is a mouse, because in mice you can check quickly enough how they age, how you can manipulate this aging process. But we also use this watch to determine, for example, the beginning of aging, that's what I told you about. This is actually the same way.

M. Astvatsaturyan – People age at different rates, that is, their biological clocks work differently, it turns out, right?

V. Gladyshev – Well, a watch is a biomarker. Here the causal relationship is not quite direct. This is some other type of watch. Biological. But if we break or remove these other clocks, we still won't change the aging process.

People can age at different rates, inside the body, different organs age slightly at different rates, and inside each organ, different cells can also age at different rates. That's why this is a very complicated process. And in this regard, I will note one of the breakthrough areas of my laboratory's work: this year we figured out how to detect aging on individual cells. We now have an article on the review, where we describe the invented first clock that determines the aging of individual cells. It seems to me that the method will also be very important in the future.

M. Astvatsaturyan – Well, since it hasn't been published yet, I can't ask for details?

V. Gladyshev – Well, I can't tell you all the details, but as if part of this work is hosted on the bioRxiv preprint server, and what is in this part of the work, I can just tell you about it.

M. Astvatsaturyan – Well, tell us two words, it's interesting!

V. Gladyshev – Well, in general, we have come up with a completely different way, an absolutely new way, such a probabilistic way of determining the biological age of individual cells. And while we have only done this on mice, we have also applied it to only a few systems so far. Well, for example, if applied to liver cells, then the main liver cell is a hepatocyte. And we see that in a four-month-old mouse, the age of most hepatocytes is also 4 months. And some cells, as we see, they are much older, and we assume that something has happened to them wrong, and therefore they age rapidly, but there are few such cells. If we take a 26-month-old mouse, we see that most of their liver cells are also 26 months old. And if we take embryonic cells, we see that their age is almost zero for individual cells. This is such a moment. But we also applied this to muscle stem cells, that is, there are a small number of cells in the muscles, they are stem cells and have not yet received their specialization

And it turned out that even in old mice, these cells are quite young. They also age, but very, very slowly.

And then we get such a model with a certain aging trajectory: if we take a tissue, we see that it ages at a certain rate. But this trajectory is different for different cells. In some cells, the so–called senescent cells (senescent cells are aging cells, they no longer renew, but do not die, but accumulate in tissues), something happens to them, they suddenly begin to age very quickly. And other cells, for example stem cells, at least some of them that we have studied and about which we know, they, on the contrary, age very slowly. And although there is a general trajectory of aging in general, it consists of many different trajectories of different cells.

M. Astvatsaturyan – And it all depends on what the general vector will be? In total.

V. Gladyshev – Yes. And the importance of this method lies in this: if we consider the aging of tissue, then we can assume that, for example, there is some small number of cells that age quickly, and on average increases the age of the tissue, and other cells simply do not age. Therefore, we need to look at aging on individual cells, and now, using these methods, we actually see that all cells in the tissue are aging, just at different rates.

M. Astvatsaturyan is an insidious question, journalistic. Do you think there is a warranty period for a person?

V. Gladyshev – Well, why is he insidious?

M. Astvatsaturyan – Well, insidious, you will now say that there is no.

V. Gladyshev – Quite a reasonable question. Yes, I have.

M. Astvatsaturyan – Yes?

V. Gladyshev – There is. Here we have a job where we calculated the maximum life expectancy of a person. But not only us, but there is also the company Gero, they also independently considered another way. It turns out approximately the same figure somewhere in the order of 130-140 years. This is probably the maximum life span of our species, man. But this is if you influence the body in some simple ways, for example, environmental factors, physical activity, food. But, of course, there are other ways when we can act more radically, for example, to rejuvenate cells.

M. Astvatsaturyan – That's what I wanted to ask about.

V. Gladyshev – Yes.

M. Astvatsaturyan – How can it be used for rejuvenation?

V. Gladyshev – I will tell you now, but to end with the fact that these 130-140 years are still the limit, which is not that it will never be possible to break it directly. Now, life expectancy is increasing, the average may be 80 years, it is gradually likely to continue to increase, maybe it will reach 90, there 100.

M. Astvatsaturyan – But are we talking about some kind of more or less acceptable, high-quality life?

V. Gladyshev – Yes, quality of life.

M. Astvatsaturyan – Yes, we do not mean absolutely decrepitude, which is prolonged and prolonged.

V. Gladyshev – Yes. Now the average life expectancy continues to increase in developed countries, although it is already high, but it still continues to increase, and it is likely to continue to increase. Nevertheless, we have a barrier further, unfortunately. New research, which is now only at the very beginning in different laboratories, is aimed at finding ways to rejuvenate the body. How to rejuvenate at least parts of the body. Make them young so that the body breaks this barrier and lives even longer.

M. Astvatsaturyan – I know that, in my opinion, you have been experimenting on the reversal of aging, on how to reverse this process, reverse it, using induced pluripotent stem cells, which are very popular now in research laboratories. I will explain to listeners and viewers: these are experimental cells that are obtained from adult cells, that is, an adult cell is taken, placed in a certain environment, where it is affected by certain factors and it turns into a stem cell, and then you can grow whatever you want from it. Well, in this case, in the case of the treatment of aging, they probably do not grow what you want, but try to rejuvenate… That's what there is, isn't it some kind of fiction at all?

V. Gladyshev – You said right, yes. So this discovery was connected with the name Shinya Yamanaka…

M. Astvatsaturyan – Yamanaki factors.

V. Gladyshev – Yamanaki factors, these are 4 genes that he expressed in adult cells, and he was able to transfer these cells into an embryonic state in this way.

M. Astvatsaturyan – That is, he took a skin cell, and got a stem cell from it, grew the retina of the eye, a person is no longer blind, for example.

V. Gladyshev – Yes. That's the idea, and they gave him the Nobel Prize for it. It's just a great discovery, the most important discovery, at least in this century, in biology.

M. Astvatsaturyan – What does it give us to prolong life?

V. Gladyshev – Does this tell us that it is fundamentally possible to rejuvenate the cell? You can take an adult's cell and make it young. Another thing is that when we do this, we transfer this cell to an embryonic state, to the state of a stem cell, it loses function.

M. Astvatsaturyan – So…

V. Gladyshev – And it is important for us to rejuvenate the cell so that it works. For example, if a cell, a hepatocyte is the same in the liver, we want it to stay and detoxify all sorts of harmful substances, and not be a stem cell. And there are a lot of laboratories working in this direction now. The idea is this: to excite the cell a little, to transfer it partially to an embryonic, but intermediate state, when it would have already rejuvenated, but then remove this effect, and it would have slipped back into its functional state.

M. Astvatsaturyan is the same in function, but young.

V. Gladyshev – Yes, the same hepatocyte, it seems to have passed into an intermediate state, rejuvenated, and then again slipped into a hepatocyte, and became as normal ....

M. Astvatsaturyan – But young.

V. Gladyshev – But young, yes.

M. Astvatsaturyan – Well, this is a very fine regulation.

V. Gladyshev – This is a very fine regulation, yes.

M. Astvatsaturyan – It's not entirely clear how to control it at all. Because there is also a problem with these stem cells of all kinds, that it is difficult to control the process.

V. Gladyshev – It's difficult, yes.

M. Astvatsaturyan – Stop in time…

V. Gladyshev – That's why research is needed. I can mention another work, it was published at the end of last year in the journal Nature. The head of the study is the head of the neighboring laboratory, David Sinclair, we work in the same building with him, and we are co-authors in this article. There, a very interesting observation turned out: mice were used as a model organism, and their optic nerve was studied. If you cut it, but the mouse loses the ability to see. And then if you express three of the four Yamanaki factors, regeneration occurs, including the rejuvenation of neurons, and the vision of this mouse is restored. And thus, it was possible to rejuvenate the cells of the optic nerve a little with these factors. There are several other works from different laboratories, where they also rejuvenated either cells in culture, or some cells in mice, while all this is being done in model organisms. In some situations, for example, when a progeroid mouse was taken, it is a mouse that lives less.

M. Astvatsaturyan – Is this a line of short-lived mice?

V. Gladyshev – Yes, and when these four Yamanaki factors were expressed in this way in it… Well, they were expressed, again, as if slightly, they are expressed for one day, then the mouse rests for 6 days. They express it again, they rest again, and that's how it is in between. And thus increased the life expectancy. That is, in reality, they were able to rejuvenate the mouse, and it lived longer. But so far this has not been done on ordinary mice, that is, on normally living ones. But this is being done now.

M. Astvatsaturyan – But it's all the same, it's insanely interesting.

V. Gladyshev – Very, very interesting. And in this regard, I would also mention here what I told you about the beginning of aging. After all, it turns out that rejuvenation occurs during embryogenesis. It turns out that the cells are rejuvenated, and if this happens, it is important to understand how it happens. Is this the same way as rejuvenation through Yamanaki factors or some completely different way? It looks like it's another way. And if we find something in common between the two methods of rejuvenation, it may be possible to induce the same changes in ordinary cells of, say, a person and thus rejuvenate them. But that's in the future. Therefore, it is very important to understand the mechanism of what happens, how rejuvenation happens, until we understand it.

M. Astvatsaturyan – It just sounds fascinating.

V. Gladyshev is fascinating, and a lot of laboratories have rushed to work on this topic now, because a very big impact will happen if this action succeeds.

M. Astvatsaturyan – If there is such an interest, so many laboratories are engaged in this, I assume that the popular science literature should be extensive. I assume that you do not know what is happening in Russia with this, what books are there on this topic… Are you often interviewed, for example, by American scientific journalists? In general, how do you see the reflection of your work in the broad format media?

V. Gladyshev – Well, yes, they do, usually when some important articles are published, yes, journalists call, contact, write something about it, or come to take interviews. Well, I don't know, I have the impression that there is probably a bigger gap between scientists and ordinary people in America than in Russia…

M. Astvatsaturyan – Is it true?

V. Gladyshev – Yes, that's my impression. And in Russia, for some reason, there are a lot more journalists and people who are engaged in scientific pop. Maybe because I'm from Russia, more interaction. But as if there is a gradient, there is no such gap between scientists and non-scientists.

M. Astvatsaturyan – This is very interesting, and it is very flattering for journalists and scientists to hear, because when we gather, we always say that we need to reduce this gap, we need scientists to be closer to the people.

V. Gladyshev – It seems to me that journalists in Russia work very well on this topic.

M. Astvatsaturyan – It is very pleasant for all of us to hear this, for our workshop. Have you come across any books recently, in America, in Russia?

V. Gladyshev – Well, do you mean books about aging?

M. Astvatsaturyan – I mean popular, for the general public

V. Gladyshev – Well, let's say David Sinclair, he released a book about a year ago, called "Life expectation".

M. Astvatsaturyan – "Life expectancy".

V. Gladyshev – Yes. And he talks about aging quite popularly there. But rather, he talks about his aging path.

M. Astvatsaturyan – In process studies?

V. Gladyshev – In research, yes. But it is well written, but in Russia I liked the book by Polina Loseva, she wrote last year about aging, a very good book came out.

M. Astvatsaturyan – Let me remind you that we talked with Professor of the Harvard School of Medicine, member of the American Academy of Sciences Vadim Gladyshev about the mechanisms of aging and longevity. Good luck to you, Vadim, in your amazingly interesting work.

V. Gladyshev – Yes, thank you.

M. Astvatsaturyan – Thank you.

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