As science proposes to postpone death.
When aging is recognized as a disease, what genes are associated with it, is there a limit to longevity and how dangerous biohacking is - in an interview with one of the winners of the “Discovery of the Year” contest, Alexander Tyshkovsky.
In December Indicator. Ru and the project “I am in Science” held a competition for the best research of Russian scientists for the year “Discovery of the Year”. According to the results of the experts' vote, one of the winners in the youth nomination of the competition was a senior researcher at the Laboratory of Systems Biology of Aging, Research Institute of Physical Chemistry, Moscow State University MV Lomonosov and Harvard Medical School Alexander Tyshkovsky with an article on the molecular mechanisms of life extension in Cell Metabolism. We talked with him about the essence of the discovery he made with his colleagues - but not only.
Alexander, tell us about your research. As far as I understand, you took the well-known methods of extending life and looked at exactly how, at the molecular level, they affect the body of mice. What did you find?
- Our main task was to understand whether the methods of life extension have some common mechanisms. To date, more than 20 different ways to increase life expectancy in animals are already known - these are various diets (for example, low-calorie), and drugs (for example, rapamycin), and some genetic influences. Among the latter, one of the most famous is a mutation that leads to growth hormone deficiency. As a result, dwarf mice are obtained, but this is already enough for them to live one and a half times longer than ordinary ones. In our work, we looked for molecular mechanisms common to all these methods. To do this, we exposed the mice to different influences and after a few months measured their level of gene activity. We were interested in how the work of genes has changed under the influence of this or that method of extending life. It turned outthe activity of about 300 genes actually changes in a similar way, regardless of the type of exposure. Moreover, it is known that different methods prolong life to varying degrees: diet, for example, by about 30%, growth hormone deficiency - by 50%, drugs - by only 10–20%. We found that the activity of some genes is related to the extent to which a particular exposure will increase the life span of an animal. That is, the more active the gene, the longer the average mouse will live, and vice versa. It turns out that the found biomarkers make it possible to estimate not only that the effect will in principle be effective, but also to draw a conclusion about how much it will increase life expectancy.growth hormone deficiency - by 50%, drugs - by only 10–20%. We found that the activity of some genes is related to the extent to which a particular exposure will increase the life span of an animal. That is, the more active the gene, the longer the average mouse will live, and vice versa. It turns out that the found biomarkers make it possible to estimate not only that the effect will in principle be effective, but also to draw a conclusion about how much it will increase life expectancy.growth hormone deficiency - by 50%, drugs - by only 10–20%. We found that the activity of some genes is related to the extent to which a particular exposure will increase the life span of an animal. That is, the more active the gene, the longer the average mouse will live, and vice versa. It turns out that the found biomarkers make it possible to assess not only that the effect will be effective in principle, but also to draw a conclusion about how much it will increase the lifespan.but also to draw a conclusion about how much it will increase life expectancy.but also to draw a conclusion about how much it will increase life expectancy.
What exactly are these genes?
- There are several hundred such genes, but many of them are involved in the same cellular processes. For example, many genes that have decreased their activity have been implicated in the immune response. Intuitively, the immune response is perceived as a useful mechanism, but in fact, with age, the activity of some elements of the immune system increases, and chronic inflammation becomes one of the factors in the development of age-related diseases. For this in science there is even a separate term inflammaging, from the words "inflammation" (inflammation) and "aging" (aging). Therefore, it is not surprising that life-prolonging treatments turn off the genes associated with this process. On the other hand, we observed an increase in the activity of genes involved in oxidative phosphorylation and glucose metabolism, that is, the receipt of energy by the cell. It was previously shownthat with age, the intensity of energy metabolism decreases in a variety of animals, including humans. Life-prolonging treatments slow this process down.
How do your results help to find new means of prolonging life?
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- Simplification of the search for new ways to prolong life is the main goal of our work. Today, in order to prove the effect of this or that effect on the lifespan of mice, it is necessary to wait for the death of animals receiving this effect and see how long they live in comparison with ordinary mice. And they live up to four years. That is, to test the effectiveness of one drug, you will have to feed a large group of mice with it all these years. This takes a lot of time and financial resources, because some drugs are quite expensive. Our results allow us to predict the effect of exposure in just two to three months, as soon as it affects the activity of biomarker genes in the body. We will be able to measure it and assess whether life expectancy will be increased. This approach makes it possible to significantly speed up and reduce the cost of the search for new influences. We are currently testing about ten of our predicted drugs for lifespan in elderly mice. I cannot draw conclusions yet, since the experiment is not finished yet, but already at this stage we see noticeable results.
Why are you interested in the topic of life extension at all?
- Honestly, I never thought about how it happened. I think there are two factors here. Firstly, I am very interested in bioinformatics and, in general, the application of mathematical methods in biology. Aging is a process in which all body systems are involved, there is no one switch that would trigger it. And it is in the study of aging mechanisms that it is most optimal to use a systems approach, and hence bioinformatics. Secondly, in my opinion, aging is one of the main problems of humanity today. Of the ten deaths on Earth, every seventh is caused precisely by age-related diseases: cardiovascular diseases, cancers, type 2 diabetes, dementia, and so on. So this is the number one health issue, and by researching aging, we are essentially working to save lives.
Is there now an established opinion in your area about how a person's life expectancy is limited? It is believed that the limit has already been reached
- There is no exact answer to this question yet. The official record is now 122 years, and there are centenarians who have lived for more than 115 years. Apparently around 120 years is the current limit that a person can reach given the current health care system, healthy lifestyles, and so on. Probably, using some kind of drugs and genetic manipulations that prolong the life of animals, we will be able to increase the average life expectancy in humans. Whether we will be able to increase the maximum in this way is a difficult question. We have some theoretical studies that show that at least up to 150 years old, it seems to work. Whether it is possible to extend life further is an open question. Of course, examples of mammals that live more than 200 years, such as whales, inspire optimism. But can a man live 200 yearswithout turning into a whale, while remaining human? In other words, can we significantly increase our lifespan without changing the key features of the structure and physiology of our body? There is no answer yet.
Are the efforts of researchers in your field aimed at aging as a whole, as a problem that humanity will solve sometime in the future, or at individual age-related diseases for which treatment is required now?
- Both approaches are applied. Some groups focus on specific age-related diseases, some of which are more popular and less popular. For example, along with the fight against cancer, the study of neurodegenerative diseases, including Alzheimer's disease, is now coming to the fore. To date, there is not a single proven drug against it in humans. With the right lifestyle, we can slightly reduce the risk of the disease, but if it has already occurred, it will not work to stop or even slow down its development. Therefore, great efforts are invested in solving this problem.
Our laboratory's approach is slightly different. Instead of fighting each disease separately, you can explore their common mechanisms of occurrence and act on them. Neurodegenerative diseases, cardiovascular diseases, and even cancer have common root causes - the accumulation of certain damage in various body systems. We see that the risk of developing all these diseases increases with very similar dynamics. And most often, by slowing the accumulation of damage in one way or another, we reduce the risk of developing most age-related diseases. Our work is aimed at finding just such a complex solution - to deal with the root causes, not the consequences.
That is, if influences similar to those that now extend the life of laboratory animals are eventually applied to humans, will they slow down the development of all these diseases or reverse them?
- More likely to slow down the accumulation of damage and delay the onset of such diseases - this is the effect of the most studied effects to date.
And which of these effects is the closest to being applied to humans?
- Medicines, since this is the simplest method of treatment. Among them are some promising antidiabetic drugs, such as the drugs acarbose and metformin. They are good primarily with few side effects. In addition, there are already studies on patients with type 2 diabetes, which showed that patients who took metformin, on average, lived even longer than healthy people without diabetes. Metformin also has beneficial effects in animals. It does not always prolong their life, but at least reduces the risk of developing age-related diseases. It is a promising candidate, and last year the first clinical trials of metformin were announced in the United States as a cure for aging, not diabetes. They will take about six years and will be held on three thousand people aged 50 and over,a variety of physiological indicators will be measured. This is an important precedent because, first, these are the first ever clinical trials of an anti-aging drug in humans. And secondly, such tests are bringing closer the day when government regulators recognize aging as a disease. Until that happens, no pharmaceutical company will be able to release an anti-aging drug for healthy people.
Which of the existing types of impacts look more promising for people?
- If we talk about the main trends in the fight against aging, I would single out two principal approaches. The first is slowing aging, which we have already talked about. And drugs give here, unfortunately, the least effect, judging by the mice. Today, the maximum that drugs can do is to increase life expectancy by 20%. Even a low-calorie diet gives up to 30%. The most effective way to slow down aging in animals is through genetic manipulation. But it is clear that in the case of humans, this is the least applicable method, because genome editing technologies are in a preparatory state and are not yet ready for use in humans, especially when it comes to prophylactic use. So existing anti-aging techniques are likely to help increase healthy longevity.but will not give a serious leap in life expectancy.
The second approach is not to slow down the accumulation of damage, but to correct them pointwise when they have already accumulated. This is the basis, in particular, of the approach of Aubrey de Gray and his organization SENS. One of the most popular startups in this area is Unity, which develops senolytics, drugs aimed at selectively destroying aged cells. Normally, cells that fail self-destruct, but sometimes this does not happen, and they remain in the tissues, although they no longer function. Moreover, these cells release inflammatory factors, which can trigger an immune response and chronic inflammation. These cells are called senescent or aged cells. And there is a hypothesis that it would be nice to remove such cells. This is what senolytics do. In experiments on mice, they extended life by about 10-15%. In humans, such drugs pass only the first stages of clinical trials, and it is too early to talk about a real effect. But if it works, it will also be one of the options.
Overall, in my opinion, our advantage lies in the fact that there are many technologies in the field of antiaging, and we do not need each of them to work. It is enough that at least a few are effective, and this will already be enough to extend your life a little. And during this time, new, more effective approaches to therapy may appear.
How do you feel about biohackers who just do not want to wait until something is guaranteed to work, and try on themselves insufficiently proven methods? Is there any responsibility of scientists here?
- You need to understand that most scientific experiments on the effectiveness of one or another method of treatment are performed on animals, and not always what works on mice will work on humans. Scientists are discovering new possibilities, and their applications in humans are being investigated by doctors after clinical trials are completed. Therefore, the responsibility of a scientist is to warn people that so far this or that approach has not been tested on a person. And as far as I know, most scientists try to do this. And then whether or not to apply this or that method is an individual decision of everyone, for which everyone is responsible for himself.
In fact, many of the techniques that biohackers use are classic well-known methods of a healthy lifestyle that have been proven to be effective in humans. For example, in moderate exercise and a low-calorie diet, there is nothing wrong if you do not go too far: do not deplete the body with hunger, do not completely abandon carbohydrates, and so on. In other cases, when the effect of this or that approach on a person has not been proven, the most important thing is to carefully weigh all the benefits and risks. For example, green tea has shown some geroprotective properties in experiments on animals. In particular, it reduced the risk of developing neurodegenerative diseases and was associated with low mortality in humans. He has no serious side effects, so I do not see anything dangerous in taking green tea: perhaps it will not prolong your life,but there will be no obvious harm from it either. And when it comes to more risky exposures with noticeable side effects, this is already worth considering. However, most of the drugs that increase the lifespan of animals are sold today only by prescription, so in some cases the government has already thought for you.
What prompted you to start popularizing science?
- I believe that one of the main tasks of scientists is to tell people about research, first of all about their own. Because if a scientist doesn't do it, someone else will. And then the study can acquire a variety of unfounded interpretations, conclusions, and so on. The area of aging in this sense is an excellent example, because there have always been many myths in it, which were not offered to people as a fountain of eternal youth. Therefore, it is especially important to talk about real research, about what has an evidence base. Yes, and I myself am always interested in performing in front of people, so popular science speeches are a great way for me to combine business with pleasure.
Do lectures and filming take a lot of time?
- More and more. On the one hand, this is great, on the other, it is becoming more and more difficult to combine this with science. With lectures in this sense it is easier, because they do not need to be rewritten every time, it is enough to supplement them with new research without changing the main content. Video is more difficult because each video needs new material. But now our team is expanding, new people are coming, and I hope this will help us do more interesting work.
Our competition was called "Discovery of the Year", and which of the recent discoveries in your field surprised you the most, seemed like news from the world of science fiction?
- I was amazed by a study last year, in which scientists for the first time managed to 3D-print an entire human heart from the patient's own cells. It was, it is true, the size of a rabbit, but anatomically it completely repeated the human. This topic is far from our laboratory, nevertheless it inspired me. The cells that became the "ink" for the printer were obtained from human adipose tissue, transformed into induced pluripotent stem cells, and then into cells of muscle tissue and blood vessel walls. Even 15 years ago, it was impossible to imagine the printing of entire organs, and in the near future this may be of great importance for transplantology - it will allow transplantation to be carried out very quickly, not to wait for a suitable donor organ, and to avoid problems with the immune response.
How can you assess the level of research in your field in Russia in comparison with the world's leading teams? Where are Russian researchers strong and where are they lagging behind?
- We have a very good school of bioinformatics. The Faculty of Bioengineering and Bioinformatics at Moscow State University, which I graduated from, prepares specialists in this field, and really strong ones. It seems to me that Russia is one of the leading countries in this area. There are difficulties in experimental biology, and they are mainly associated with the high cost of experiments on animals. In the field of aging, they require particularly large resources. As we discussed, testing a drug for life extension in mice requires giving it every day for about four years. And drugs are expensive, and the groups of mice should be rather big: dozens of animals in both the control and experimental groups. In the United States, there is a separate state program for such experiments, sponsored by the Department of Health,as no single laboratory can afford it. So in terms of animal experiments, we are losing, but our strong point is in mathematics and computer science. Therefore, it is very important to continue to support the training and work of such specialists. In general, science today has no territorial boundaries. So in the fight against aging, we are all doing a common cause.
Author: Ekaterina Erokhina
