How science suggests delaying death
"Can a person live for 200 years without turning into a whale?"
Ekaterina Erokhina, Indicator
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 expert voting, Alexander Tyshkovsky, a senior researcher at the Laboratory of Systems Biology of Aging at the Lomonosov Moscow State University and Harvard Medical School, was recognized as one of the winners in the youth nomination of the competition with an article on molecular mechanisms of life extension in Cell Metabolism (Tyshkovsky et al., Identification and Application of Gene Expression Signatures Associated with Lifespan Extension).
We talked with him about the essence of the discovery he and his colleagues made – but not only.
– Alexander, tell us about your research. As far as I understand, you took the well-known methods of prolonging life and looked at how exactly at the molecular level they affect the body of mice. What was discovered?
– Our main task was to understand whether the methods of life extension have some common mechanisms. To date, there are already more than 20 different ways to increase life expectancy in animals – these are various diets (for example, low-calorie), medications (for example, rapamycin), and some genetic effects. Among the latter, one of the most famous is a mutation that leads to a deficiency of growth hormone. As a result, dwarf mice are obtained, but this is enough for them to live one and a half times longer than normal. In our work, we looked for molecular mechanisms common to all these methods. To do this, we exposed mice to various influences and after a few months measured their level of gene activity. We were interested in how the work of genes changed under the influence of a particular method of prolonging life. It turned out that the activity of about 300 genes does change 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%, medications – by only 10-20%. We found that the activity of some genes is related to how much this or that exposure will increase the life expectancy of an animal. That is, the more active the gene, the longer the mouse will live on average, and vice versa. It turns out that the biomarkers found allow us to assess not only that the effect will be effective in principle, but also to conclude how much it will increase life expectancy.
– What exactly are these genes?
– Several hundred such genes have been found, but many of them are involved in the same cellular processes. For example, many genes that decreased their activity were involved 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. There is even a separate term for this in science, from the words "inflammation" (inflammation) and "aging" (aging). Therefore, it is not surprising that life-prolonging effects 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, energy production by the cell. It was previously shown that with age, the intensity of energy metabolism decreases in a variety of animals, including humans. Life-prolonging effects can slow down this process.
– How do your results help to find new means of prolonging life?
– Simplifying the search for new ways to prolong life is the main goal of our work. Today, in order to prove the effect of one or another effect on the lifespan of mice, it is necessary to wait for the death of animals taking this effect and see how long they will live compared to ordinary mice. And they live up to four years. That is, to test the effectiveness of one drug, you will have to feed a considerable group of mice with it all these years. It takes a lot of time and financial resources, because some medicines 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 searching for new impacts. At the moment, we are testing about ten drugs we predicted for life expectancy in elderly mice. I can't draw conclusions yet, since the experiment is not over yet, but already at this stage we see noticeable results.
– Why are you interested in the topic of life extension at all?
– To be honest, 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 the systems of the body are involved, there is no one switch that would trigger it. And it is in the study of the mechanisms of aging that it is most optimal to use a systematic approach, and therefore bioinformatics. Secondly, in my opinion, aging is one of the main problems of humanity today. Out of ten deaths on Earth, every seventh is caused by age-related diseases: cardiovascular diseases, cancers, type II diabetes, dementia, and so on. So this is the number one problem in healthcare, and by researching aging, we are, in fact, working to save people's lives.
– Is there a well-established opinion in your field now, what is the limitation of a person's life expectancy? There is an opinion that the limit has already been reached.
– There is no exact answer to this question yet. The official record is now 122 years old, and there are centenarians who have lived for more than 115 years. Apparently, about 120 years is the current limit that a person can reach given the current healthcare system, healthy lifestyle, and so on. Probably, using some medications 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, apparently, it will work out. Whether it is possible to prolong life further is an open question. Of course, the examples of mammals that live more than 200 years, such as whales, inspire optimism. But can a person live for 200 years without turning into a whale, while remaining human? In other words, can we significantly increase our life expectancy without changing the key features of the device 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 that require treatment now?
– Both approaches are applied. Some groups focus on specific age-related diseases, among them there 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 help of a proper lifestyle, we can slightly reduce the risk of the disease, but if it has already occurred, it will not be possible to stop or even slow down its development. Therefore, great efforts are being invested in solving this problem.
Our laboratory's approach is a little different. Instead of fighting each disease individually, you can investigate their common mechanisms of occurrence and act on them. Both neurodegenerative and cardiovascular diseases, and even cancer have common root causes - the accumulation of certain damage in a variety of body systems. We see that the risk of developing all these diseases increases with very similar dynamics. And most often, by slowing down 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 comprehensive solution – to deal with the root causes, not the consequences.
– That is, if the effects similar to those that now prolong the life of laboratory animals are eventually applied to humans, will they slow down the development of all these diseases or reverse them?
– Rather, they will slow down the accumulation of damage and delay the occurrence of such diseases – this is the effect of the most studied effects to date.
– And which of these effects are closest to application in humans?
– Medications, because this is the simplest method of treatment. Among them there are some promising antidiabetic drugs, such as acarbose and metformin. They are good primarily with a small number of side effects. In addition, there are already studies on patients with type 2 diabetes, which have shown that patients who took metformin, on average, lived even longer than healthy people without diabetes. Metformin also has positive effects on animals. It does not always prolong their life, but at least reduces the risk of developing age-related diseases. This is a promising candidate, and last year in the USA it was announced that the first clinical trials of metformin were launched as a cure for aging, not for diabetes. They will take about six years and will be conducted on three thousand people from 50 years and older, a variety of physiological indicators will be measured. This is an important precedent, because, firstly, this is the first ever clinical trials of an anti-aging drug on a person. And secondly, such tests bring closer the day when state regulators recognize aging as a disease. Until this happens, no pharmaceutical company will be able to produce 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 fundamental approaches. The first is the slowing down of aging, which we have already talked about. And drugs give here, unfortunately, the least effect, judging by the mice. To date, 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 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 preventive use. So the existing methods of slowing down aging are likely to help increase healthy longevity, but will not give a serious jump in life expectancy.
The second approach is not to slow down the accumulation of damage, but to fix them point-by-point when they have already accumulated. This is the basis, in particular, of the approach of Aubrey de Grey and his organization SENS. One of the most popular startups in this field is Unity, which develops senolytics – drugs aimed at the selective destruction of 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, such cells secrete inflammatory factors, and this can cause an immune response and chronic inflammation. These cells are called senescent, or aged. And there is a hypothesis that it would be good to remove such cells. This is what senolytics do. In experiments on mice, they prolonged 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 the real effect. But if it works, it will also be one of the options.
In general, in my opinion, our advantage lies in the fact that there are many technologies in the field of anti-aging, and we do not need each of them to work. It is enough for at least a few to be effective, and this will already be enough to prolong your life a little. And during this time, new more effective approaches to therapy may appear.
– How do you feel about biohackers who just don't want to wait until something is guaranteed to work, and try insufficiently proven methods on themselves? Is there any responsibility of scientists here?
– You need to understand that most scientific experiments on the effectiveness of a particular treatment method are performed on animals, and not always what works on mice will work on humans. Scientists are opening up new possibilities, and doctors are engaged in their application in humans after clinical trials have been 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 it. And then to apply or not this or that method is already 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 healthy lifestyle techniques that have proven their effectiveness in humans. For example, there is nothing wrong with moderate exercise and a low-calorie diet, if you do not overdo it: do not exhaust the body with hunger, do not completely abandon carbohydrates, and so on. In other cases, when the effect of one or another approach on a person has not been proven, the most important thing is to carefully weigh all the benefits and risks. For example, in animal experiments, green tea has shown some geroprotective properties. In particular, it reduced the risk of neurodegenerative diseases and was associated with low mortality in humans. It has no serious side effects, so I don't see anything dangerous in taking green tea: it may not prolong your life, but there will be no obvious harm from it either. And when it comes to more risky effects with noticeable side effects, it's already worth thinking about. However, most of the medicines that increase the life expectancy of animals are sold today only by prescription, so in some cases the state has already thought for you.
– What prompted you to popularize science (Alexander is the founder and host of the YouTube channel Real Scientists – Indicator.Ru)?
– I believe that one of the main tasks of scientists is to tell people about their 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 unreasonable interpretations, conclusions, and so on. The field of aging in this sense is a great example, because there have always been a lot of myths in it, which has not been offered to people as a fountain of eternal youth. Therefore, it is especially important to talk about real research, about what has an evidentiary basis. And I myself am always interested in performing in front of people, so popular science performances are a great way for me to combine business with pleasure.
– Do lectures and filming take up a lot of your time?
– More and more. On the one hand, it's great, on the other – it's getting harder to combine it with science. In this sense, it is easier with lectures, because they do not need to be rewritten every time, it is enough to supplement them with new research without changing the main content. The video is more difficult, because each video needs new material. But now our team is expanding, new people are coming, and I hope that this will help us do more interesting work.
– Our contest 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 struck by a study last year in which scientists for the first time managed to print an entire human heart from the patient's own cells on a 3D printer. It was, however, the size of a rabbit, but anatomically completely repeated the human. This topic is far from our laboratory, however, it inspired me. The cells that became "ink" for the printer were obtained from human adipose tissue, turned 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 whole organs, and in the near future it may be of great importance for transplantology – it will allow transplants to be carried out very quickly, not to wait for a suitable donor organ, 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 collectives? In what are Russian researchers strong, and in what are they lagging behind?
– We have a very good school of bioinformatics. The Faculty of Bioengineering and Bioinformatics of Moscow State University, which I graduated from, trains 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 animal experiments. In the field of aging, they require particularly large resources. As we discussed, to test some kind of life-prolonging medicine on mice, you need to give it every day for about four years. And medicines can be expensive, and groups of mice should be rather big: dozens of animals in both the control and experimental groups. In the USA, there is a separate state program sponsored by the Ministry of Health for such experiments, since no single laboratory can afford it. So in terms of animal experiments, we are losing, but our strength 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.
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