How to cure aging?

Member-correspondent. RAS Alexey Moskalev: "Aging is a disease that must be learned to treat"

Natalia Leskova, "Scientific Russia"

Are there genetic mechanisms of aging and longevity? Is it possible to influence them by increasing their life expectancy? What can we learn from long-lived organisms? Do we even need to live long? What can we do today to get less sick and feel better? Alexey Alexandrovich Moskalev, Doctor of Biological Sciences, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Geroprotective and Radioprotective Technologies at the Institute of Biology of the Ural Branch of the Russian Academy of Sciences, a leading researcher at the Institute of Molecular Biology. Engelhardt and the Vavilov Institute of General Genetics.

– Alexey, you are engaged in such an intriguing and relevant topic for everyone as the genetics of aging. What is this direction?

– Initially, scientists assumed that certain genetic inclinations can affect the rate of aging. On the one hand, we see the so-called accelerated aging syndromes, when, as a result of certain mutations, people at a very young age acquire some signs of decrepit old age and age-dependent diseases (for example, cardiovascular) – this is Hutchinson-Guilford syndrome, Werner syndrome, and so on.

And on the other hand, we know about the so-called family, hereditary longevity, when people living to ninety, one hundred, one hundred and ten years are likely to meet in the same family.

Indeed, in such families, the probability of longevity is much higher than the average. This was the basis of the assumption about the hereditary nature of slowing down aging and longevity.

In addition to observational studies on humans, studies on model animals were also conducted back in the twentieth century, for example, breeding for late fecundity of fruit flies of fruit flies. Back in the 80s, it was shown that such selection after several generations leads to the creation of long-lived animal lines. That is, if compared with the parent line, they can live many times longer. Selection for a longer reproductive lifespan was accompanied by selection for overall longevity.

– That is, it is possible to regulate these processes on fruit flies?

- Yes. But then, when molecular biology and methods of breeding lines, targeted mutations in the animal genome were developed, this made it possible to create long-lived model animals by the end of the 80s, already targeting mutations in certain genes.

Such a breakthrough was achieved on the model of the nematode Caenorhabditis elegans, since then it has been a favorite object of research in the genetics of aging. It turned out that switching off, that is, a decrease in the activity of certain genes, led to an increase in the lifespan of the lines of these animals by two or even more times.

So it was proved that by influencing the activity of one particular gene at one time, it is possible to achieve such outstanding effects that increase life expectancy beyond the species limit.

– Have there been any side effects?

– Everyone wants not just to prolong life, but also youth, to delay diseases. Using the example of long-lived people, we just see that such people acquire disability and many chronic diseases on average twenty years later, and some, such as oncology or diabetes mellitus, are generally rare among centenarians. And this tells us that the general slowing down of aging prolongs a healthy period of life. There were different options for animals. We know that nematodes with the insulin-like growth factor receptor gene turned off are smaller in size, respectively, their motor activity is less, while their life expectancy increases.

– Is there such a pattern in humans? After all, centenarians, as I understand it, are not obese and are shorter?

– Yes, there are such studies, they were conducted on Ashkenazi centenarians in New York, at Albert Einstein College, and they showed that indeed, the activity of the insulin-like signaling pathway is also reduced in centenarians. Interestingly, we also made a certain contribution to this topic with a colleague from Harvard Medical School, Vadim Gladyshev.

We planned to study Brandt's nocturnal at the time. It is the smallest long-lived mammal. With an average body weight of seven grams in the wild, she can live up to more than forty years.

– How was it shown?

– Novosibirsk zoologists caught and ringed individuals, released them into nature, then some of them got back into the nets, were released again. And so for dozens of years of observations it turned out that some live up to 42 years, maybe even more, I just don't have more recent statistics.

But we were very interested in this fact, and my Institute of Biology, under my leadership, organized a series of expeditions in which we caught individuals in the wild in different seasons of the year, because bats hibernate, hibernate. It was interesting for us, in addition to the genome, which my colleagues and I decoded for the first time, to also study the transcriptome, that is, the activity of genes in different tissues and in different seasons of the year.

When the genome was collected and studied, it turned out that Brandt's bats also have certain deletions and substitutions in the genes of the growth hormone receptor, or the insulin-like growth factor receptor. That's why they are so small and long-lived at the same time.

– Maybe it is worth influencing this factor in a person, or is it unethical?

– This is a question that is now being asked not only by scientists, but also by startups that are developing interventions aimed at aging, age-dependent diseases.

It turned out that a certain lateral branch of this insulin signaling pathway is the kinase cascade mTOR. This is a switch in the cell, which, depending on the presence of amino acids in the nutrition of the cell, intensively activates protein biosynthesis. As a result, the cell grows, divides, and increases in size.

But under conditions of amino acid starvation, or protein starvation, as we usually call it, mTOR turns off and unblocks the processes of autophagy – this is the self-digestion of cell structures. These autophagy processes are needed to release the necessary set of amino acids from internal reserves. But at the same time, damaged mitochondria, aggregates of oxidized proteins go into the furnace, and the cell is rejuvenated from the inside.

Almost since the beginning of the twentieth century, it has been known that periodic fasting, a decrease in caloric intake lead to an increase in life expectancy. This is one of the mechanisms of aging, mTOR reduces its activity while, accordingly, the processes of recycling damaged structures inside the cell are activated, the cell is rejuvenated in this way a little.

– So, regulated fasting is one of the mechanisms for prolonging life. What else can help?

– Certain inhibitors of this enzyme mTOR were already known to medicine. And if we pharmacologically reduce activity without resorting to starvation, then, at least in mice, this also allowed us to significantly increase life expectancy. Now it is repeatedly reproduced data by different researchers on different lines of mice. An increase in life expectancy has been achieved by up to 25%. However, there are certain side effects, because protein biosynthesis is required for, for example, the immune system. Therefore, this inhibitor is an immunosuppressor. It is used for organ transplantation so that there is no rejection.

– We talked about the fact that many long-lived organisms are very small, this applies to naked diggers, and blind people, and bats. But, for example, the whale, which you also studied, has huge dimensions. Why is he a centenarian?

– Yes, that's why the next model that interested us very much was the whales. At that time, the bowhead whale had already been studied. Thanks to cooperation with colleagues from the Institute of Molecular and Cellular Biology of the Siberian Branch of the Academy of Sciences, we have samples of gray whale tissues. The bowhead whale is just the record holder for longevity, recorded at the moment among all mammals. There is some indirect evidence that they can live from one hundred and fifty to even two hundred years.

But the gray whales are smaller, but they are still long-lived and were not genetically studied at that time, and we had their samples. We jumped at this opportunity. With colleagues from the Institute of Molecular Biology, we sequenced the genome, transcriptomes in different organs, and in a large collaboration of bioinformatics specialists from Israel and Romania, we analyzed the activity of genes. In addition to the fact that we decoded the genome, published it, we read the transcriptome, that is, a set of matrix RNAs. And we compared the activity of the genes of different whales in certain organs, that is, our gray whale, bowhead whale, tabby (this is an even smaller whale and lives even less).

– So there is an inverse relationship here?

– Yes, and it's very interesting. So, we analyzed their transcriptomes and compared them with the activity of cows' genes, because they are evolutionarily the closest terrestrial relatives of cetaceans. Once upon a time, a group separated from the ungulates, which switched to an aquatic lifestyle, lost limbs.

By the way, the gray whale also turned out to be interesting from an evolutionary point of view, because it has the oldest signs – it still has whiskers on its muzzle, the remains of the bones of the hind limbs. Moreover, unlike other whales, it does not move far from the coast, it migrates along the coast, so its migration reaches ten to twelve thousand kilometers per year. He is very hardy, he overcomes huge distances. And this is because he sails along the coast – this path is longer than if you cut across the ocean.

In this study, we compared transcriptomes with a naked digger, a long-lived rodent, with a human and with Brandt's bat, and with mice, rats as representatives of short-lived mammals.

– What did you find out?

– It turned out that long-lived mammals and especially whales have more active DNA repair genes. We know that a nuclear DNA molecule has only two copies in a cell, and if something breaks in the DNA, this cell either dies, or is reborn into some atypical cell, or stops dividing, and thereby tissue regeneration stops. It is very important to preserve the integrity of DNA. And for this, there are certain enzymes that restore the integrity of DNA. It is clear that the effectiveness of this recovery affects longevity.

The second most important factor that we have seen is the so–called ubiquitination of proteins. This is a mechanism for maintaining the constancy of the protein composition, when a kind of label is put on oxidized, damaged, unnecessary cells, and this leads to the fact that they go for disposal. Proteostasis, that is, the constancy of the protein composition, is also a very important component of longevity.

The third factor is autophagy, and this is the process of self–purification, elimination of damaged mitochondria, some membrane components, whole aggregates of oxidized proteins. This is also a process related to longevity.

And the fourth is immunity, because if you live for a long time, the probability of catching an infection is high. If you have a strong immune system, you survive it all safely and remain a long-lived person. If the immune system is weak, then, accordingly, it is more difficult to live to old age.

– Are these mechanisms universal for all long-lived organisms or are they different?

– Nature can come to a similar result in different ways. The specific genes by which this is achieved may vary from species to species, but these processes play a crucial role, as we can see from the example of an experiment that nature itself conducted on the longest-lived mammals. All whales are in the top ten long-lived, although humans are also in this top ten, which is nice.

– But everything is not enough for a person, he does not think that it is enough for him. What other scenario can we follow, besides what you have already said, in order to achieve a longer longevity than now?

– In scientific terms, it would be interesting, for example, to decipher the genome of the Greenland shark, which lives, as is now confirmed, up to four hundred years. She, of course, is cold-blooded, they are evolutionarily far from us, and the very fact of cold-blooded slows down their metabolism. But a Greenland shark would be very interesting. They have a very high level of urea in their blood, because the excretory system is arranged in a certain way. By the way, it is known that people with Gilbert's syndrome, when urea levels are elevated, are less likely to suffer from cardiovascular diseases. Of course, this is our hypothesis, but it seems to me that there is something in it, and I would like to study it further. If we somehow delay or slow down the processes associated with cardiovascular diseases, we will significantly prolong the life of the population as a whole.

– How will science move in order to prolong human life? What pharmaceutical, bioengineering, genetic engineering methods will appear in the not very distant future?

– I would like to take an active part in this, and we have relevant projects where we are trying, based on our knowledge of the mechanisms of aging and longevity, to make important steps. There are mechanisms of longevity, autophagy, ubiquitination, DNA repair, there are mechanisms of aging, such as glycation, chronic inflammation, which is the basis of all age–dependent diseases, oxidative stress is also a mechanism of aging. All these processes are controlled by certain enzymes. We do not have answers to all the mechanisms of aging in the body itself, because there was no task for evolution to make an immortal individual, but there was a task to prolong life sufficiently from the point of view of reproductive lifespan to have time to pass on their genes to as many descendants as possible.

Now there are, for example, technologies for the specified construction of proteins. Enzymes that do not exist in nature are created in order to catalyze certain processes biotechnologically. Theoretically, it is possible to come up with some enzymes that will intercept metabolic errors associated with aging processes, to which nature has not so actively turned its attention evolutionarily. Understanding these mechanisms, it is possible to target, purposefully influence them.

If we know the genome of a particular person and understand what the breakdown is, then with the help of gene therapy we can introduce a whole version of the gene and correct the defect, at least in the part of cells that will receive this vector and express an already healthy version of the gene. This will delay the risks of chronic diseases, including cardiovascular diseases.

– Do you think this is how healthcare will develop?

– It's quite possible.

– Alexey, I periodically hear from some scientists the point of view that there are immortal organisms. For example, trees that collapse under the weight of their own weight and only die because of this, and not because they have grown old. Is this so, in your opinion, or is immortality in principle impossible?

– As for the aging and longevity of plants, this is also our favorite topic. We just recently published an article with Konstantin Krutovsky from Germany and at the same time from the Institute of General Genetics, with Vasily Popov from Voronezh Technological University and Claudio Franceschi, a well-known gerontologist from Italy, where we summarized all the mechanisms of aging and longevity of plants known to date.

It turned out that the plants came up with a lot of things due to the fact that they have nowhere to run, they were born where they came in handy. Therefore, they have other survival strategies, and they have allowed them to develop such longevity. Of course, there are no immortal organisms, because the very concept of "immortality" presupposes the absence of death, and accidents can also be the causes of mortality.

But there are slowly aging or, as they are also called, insignificantly aging, "negligible senescence" organisms. There are really a lot of plants among them, there are coniferous species that live up to eight, up to ten thousand years. By the way, an interesting hypothesis suggests itself here, because sequoias are gigantic, and their gigantism is due, among other things, to the fact that their ancestors once had a hexaploidization of the genome. The cell acquired six copies of the nuclear genome, and biosynthetic processes began to take place at another level, which may have led to their gigantic size.

But at the same time there was a backup of the genome. We said that damage to the DNA molecule is fraught with serious consequences for the cell. And if you have six copies, there is already a place to turn around, and the margin of safety increases.

– That is, here we also have something to explore and learn.

- Yes. Plants also have photosynthetic processes, and they are accompanied by a huge release of free radicals. Antiradical mechanisms in plants are laid down by nature itself.

– While a huge number of scientists are looking for ways to prolong life, there are scientists who believe that we do not need it at all. Well, for example, your colleague Pyotr Chumakov from the Institute of Molecular Biology recently told me that we should not strive to artificially prolong life, because the continuation of our life is students, children, this is exactly what nature intended, and we do not need to try to deceive her. What do you think about this?

– I adhere to this point of view: aging is akin to a disease, it is a set of pathological processes. Pathological genetic chains react inadequately to some metabolic errors, such as inflammation. We know that it is very useful in order to survive infections or injuries. But if this process does not slow down, then chronic inflammation leads to cardiovascular, oncological, neurodegenerative diseases. This, in fact, is aging, unstoppable pathogenetic processes that lead to diseases and death.

– So aging is a disease that we must learn to treat?

- Yes. Centenarians, as we said, acquire disability and chronic diseases twenty years later, that is, they live with a much higher quality of life. And finally, if we try to treat diabetes mellitus, sarcopenia, or some other diseases, we do not succeed, because we do not hit the target, and the goal is aging. Aging is a risk factor for all chronic infectious diseases. As the covid shows, the age factor is the determining factor in mortality risks. For this reason, if we study aging, longevity, and use this knowledge to apply to a person, we will first of all prolong a healthy period of life.

– What do you think is the real age limit for a person?

– I can only say that by acting on the causes of aging, we can postpone the risks of diseases and mortality: what to die from if you are healthy, right? Therefore, of course, this will lead to a radical extension of a healthy period of life.

– What do you do yourself in order to live for a long time?

– So far, all we have is a healthy lifestyle. It consists of several components. First of all, it is, of course, the absence of bad habits, because both alcohol and tobacco smoking are the most powerful risk factors for accelerated aging and a large number of chronic diseases. At the same time, proper nutrition and regular physical activity are important, and they should be evenly distributed, not just the gym on certain days of the week. It is even necessary to just walk, walk, not sit, even at the workplace to take breaks all the time, some kind of warm-up. Vascular aging, stagnation in the venous system, problems with microvessels, with capillaries develop against the background of a sedentary lifestyle, which carries a huge number of risks.

Accordingly, monitor the body fat mass. Now you can even measure it in the gym with the help of bioimpedance and keep it normal. Visceral fat around blood vessels, around vital organs is a powerful source of inflammatory cytokines that lead to chronic diseases.

– It is known that long-lived organisms are also resistant to chronic stress. How do you train stress resistance in yourself?

– It consists of many components, it exists even at the cellular level. Resistance, for example, to temperature changes, and here you can do with hardening, for example, periodically swim in the pool. Going to the sauna regularly – elevated temperature also stimulates our protective systems. There is even such a concept as "hormesis", when moderate stress counteracts metabolic errors, because it includes internal mechanisms of stress tolerance, error elimination. If you periodically turn on these mechanisms, if you do not leave them to gather dust and mold, then this leads to longevity.

Of course, healthy sleep is important, because during sleep, the process of regeneration of the immune and nervous systems takes place, even DNA is repaired in neurons. Those who do not get enough sleep have a higher risk of diseases.

– And some events that traumatize us and that also cause significant stress – how do you cope with this?

– It is important to understand here that periodic stresses, which are moderate, are useful. If we are talking about severe or chronic stress, then the reserve mechanisms of stress resistance are depleted, and the accumulation of errors increases exponentially. As for psychological things, I adhere to the concept of stoicism. This concept has been around for more than two thousand years, and it works: we have to do everything that depends on us. But not everything depends on us, and the rest needs to be "let go".

– Do what you must, and come what may?

– Yes, as Marcus Aurelius said, he is also a Stoic. By the way, in the Bhagavad Gita exactly the same words were said many years before even Marcus Aurelius himself.

It's difficult, it's worked out by training. But when this is achieved, then you look at many things quite differently. Of course, there are techniques – meditation, breathing methods that allow you to train your stress resistance, when you learn to control your thoughts, concentrate your attention and perceive reality better.

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