An interview with biologist Vadim Gladyshev on the causes of aging and the prospects for prolonging life
The Laboratory for Systems Biology of Aging was opened at the N. N. Belozersk Moscow State University in 2017 funded by a grant from the government of the Russian Federation. It is led by a graduate of Moscow State University, professor at the Harvard School of Medicine Vadim Gladyshev. "Attic" asked him about why we are getting old, what to do with it, and what his colleagues in Russia and the United States are doing.
There are quite a few concepts of aging. Let's look at this process first on a small, cellular level. How would you define an old cell?
- From my point of view, aging is the accumulation of harmful changes with age. This is not only molecular damage, changes can be different: there may be an excess or insufficient amount of some component, or a cellular imbalance, or some other changes. For example, in the composition of the protein complex, one protein is more than necessary, and the other is not enough. These changes accumulate with age. This applies to both the cell and the organism, because most unicellular organisms age as well as multicellular organisms, there is not much difference. But in a multicellular organism it is more difficult, because different organs and different cells inside organs age in it, and they somehow interact with each other. Different organs can age at different rates, different cells can age at different rates, and they all affect each other.
Is there some kind of border by which you can distinguish an old cage from an old one?
- No, it's such a continuous process. Aging actually begins with fertilization. The egg was fertilized, a new organism arose and immediately began to age. It's just that there is a high mortality among the embryos, so damage is not yet visible against the background of everything else. This actually manifests itself only after nine years, in the case of humans, when mortality begins to rise with age.
Can you single out a key cause of aging?
- That's the problem. It is not clear how to make an experiment that would reflect the transition of the entire system to the old state, and not some of its parts. Usually they take some part, for example, some one gene or organelle, and look at them, trying to understand aging. But this cannot fully reflect the aging picture of the whole organism.
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So we can't take any single factor and call it the cause?
- There is no main reason for aging. It cannot exist in principle. Imagine the following situation: some factor has become limiting. Here it is - the main reason for aging, because of it everything gets old. Natural selection can then be expected to weaken for all other components. Let's say that there is some other protein that works very well, it does not break down, and it functions all life. And a mutation arose in him, he became a little worse because of this. But it will not matter, it will not be eliminated by selection, because another reason for aging is still limiting. Then a mutation arose in another gene, in a third … Everything will gradually get worse and worse until it is synchronized with the factor that was the main factor in our beginning. As a result, again, many factors will act together on aging, and there will not be one main one. But the synchronization will not be perfect,and this manifests itself differently in different species. Mice, especially laboratory ones, often die from certain types of cancer, and humans die from heart disease. This happens because the synchronization of the extinction processes is not absolute; there is a different predisposition for age-related diseases.
How unambiguously is the aging of cells and aging of the organism connected? Suppose we have a naked mole rat that practically does not age. At the same time, you recently wrote that some mechanisms of aging were found in it. Does this mean that individual cells are subject to aging, but the mole rat himself is not?
- No, that's not entirely true. I think the digger is getting old too. He just lives for a very long time. And because our damage is all accumulating together, it's hard to find the root cause. But sometimes you can manipulate some kind of reference protein that affects many other processes. Let's say we removed it - everything has changed, the body has become different and now it ages a little differently and can age longer. So it is with the excavator: it ages longer, and it ages for so long that it is very difficult to notice this process.
But do individual aging cells in his body still accumulate?
- Sure. For example, it has neurons. They are formed during embryonic development. Then they are not replaced, they are non-renewable cells. Sometimes something happens in them, for example, a mutation has occurred or some other error - the neuron has died, and it cannot be replaced in any way. Some time has passed - another neuron dies, another, a third. It turns out that the body cannot but age. This applies to any mammal.
Vladimir Skulachev and co-authors put forward the assumption that the mole rat is a neotenic mouse (that is, one in which development is greatly slowed down, so individuals begin to reproduce in childhood - author's note), and a man is a neotenic monkey. Therefore, a mole rat ages more slowly than a mouse, and we - more slowly than monkeys. Do we have any mechanisms of our own that allow us to age more slowly?
- This is an interesting question. We have a project on this topic in the Moscow laboratory. We are just trying to discover at the level of evolutionary processes some common features between man and mole rat in comparison with their closest relatives, which are not neotenic. On the fly, the genes responsible for these processes are not found, but we are still looking.
Is there a chance that we can borrow some mechanism of longevity from the digger?
- Yes, this is one of the main ideas in my laboratory. We want to study long-lived organisms, including the mole rat, and somehow use the mechanisms that have arisen in them during evolution. But for people this is not a question of tomorrow, of course, because first you need to check on mice.
Diagram of the comparative life span of various animals. [A] Maximum life span, taken in relation to the mass of an adult; [B] Examples of long-lived species; [C] Comparative location of some mammalian species in relation to their average life span. Illustration from an article by Siming Ma, Vadim N. Gladyshev. Molecular signatures of longevity: insights from cross-species comparative studies / Seminars in Cell & Developmental Biology.
Which of the life extension strategies do you think has the most chances in the near future?
- One trend is simple interventions like calorie restriction, they are already there, they can be tested. Attracting mechanisms from long-lived organisms is a second, longer-term trend, with the potential for more drastic changes in lifespan. Conventional simple interventions in mice prolong life by 20-30% maximum. If transferred to a person - and most likely [such interventions] will not work so well for him - this is an increase in [life expectancy] by 10 or 20 years, ideally. And there is a third option - it is completely new, only one article on this topic has been published, there is still little data here - this is rejuvenation in vivo, inside the body, when the so-called "Yamanaka factors" can be expressed. These are four transcription factors that allow a cell to move from an adult to an embryonic state. This work came out a year ago. There, scientists expressed these four genes in mice, some of the cells passed into a younger state, and the mouse began to live longer. But the problem is this: when we rejuvenate the cell, we greatly increase the likelihood of cancer. Therefore, in that work, they cheated a little, or something: they made an experiment on a short-lived line of mice, which did not have time to develop cancer. But in principle, this is a very good idea. You can simultaneously rejuvenate and fight cancer, combine these strategies. This area has great potential. I have heard from several laboratories that research is currently underway on this topic.we greatly increase the likelihood of cancer. Therefore, in that work, they cheated a little, or something: they made an experiment on a short-lived line of mice, which did not have time to develop cancer. But in principle, this is a very good idea. You can simultaneously rejuvenate and fight cancer, combine these strategies. This area has great potential. I have heard from several laboratories that research is currently underway on this topic.we greatly increase the likelihood of cancer. Therefore, in that work, they cheated a little, or something: they made an experiment on a short-lived line of mice, which did not have time to develop cancer. But in principle, this is a very good idea. You can simultaneously rejuvenate and fight cancer, combine these strategies. This area has great potential. I have heard from several laboratories that research is currently underway on this topic.
“But in this case, we may have a problem that we are slower to learn to fight cancer than to reprogram cells
- Why, in the case of cancer, there has also been very great progress in recent years. Cancers are now sequenced, the main drivers have been found for each type of cancer, and inhibitors are selected for these drivers. Previously, the treatment was simple: chemotherapy or radio - and hello, it's the same for everyone. And now they take cancer, sequenced and already know which inhibitor to take, which acts on the very gene that confused. This is a completely different level.
Author: Polina Loseva
