Scientific biohacking
Hacking the aging program. Interview with M.Skulachev
Anastasia Ibragimova, "Scientific Russia"
Maxim Vladimirovich Skulachev, Associate Professor of the Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University, CEO of the innovative pharmaceutical company Mitotech.
The question of eternal or, at least, long youth attracts many. Can a person not only feel himself, but also really be healthy and young, regardless of the date of birth indicated in the passport? In an interview for "Scientific Russia" Maxim Vladimirovich Skulachev, associate professor of the Faculty of Bioengineering and Bioinformatics of Moscow State University, CEO of the innovative pharmaceutical company "Mitotech" told why youth leaves, how African rodents manage to maintain "embryo health" for a lifetime of almost 40 years, how scientists explain the phenomenon of old age and that each of us he can do everything to get on the path of improving his quality of life right now.
– Maxim Vladimirovich, please tell us where we are now?
– We are located in one of the laboratories of our company's project, this is part of the production – the laboratory of fine organic synthesis. The very substances on the basis of which we make our medicines are synthesized here. This is where it all starts: this is the most "holy of holies" of our project. Then prototypes of drugs appear, they are tested on animals, in clinical studies – already on volunteers and even then they are released in pharmacies.
– For many, making youth a reality is a very big dream. But before moving on to the question of youth, it is very difficult to avoid the question of old age. Why does a person age, and how many scientists have thought about the topic of aging?
– A completely honest answer to the question "Why are we getting old?": no one knows. But we are definitely doing it. We're getting old. This has been noticed for a long time. And here, oddly enough, unacceptably little has been done in science about this. In general, the biologist was somehow ashamed to deal with the topic of aging until recently. I don't even know why. Whether it was somehow connected with thanatophobia, because in the end life ends very badly – death. And studying it is somehow unpleasant, scary, then - it concerns all of us: we are all getting old. Maybe people somehow transferred it to themselves and therefore… I can't explain it. But I must say that gerontology is one of the weakest areas of biology. And here, in many ways, we can say that scientists owe us all, the whole society, quite a lot. But the situation has changed, I would say, in the last 15 years. Now gerontology is the science of aging, precisely as an engineering science, as a science trying to offer some kind of solution, "slowly" turns into the "mainstream". This is very cool, it makes me very happy, because it means that scientists have felt something.
If we return to your question "Why are we getting old?", there is a classical point of view. I think it is categorically wrong, but as an honest person I have to voice it. The classical point of view is that we just "wear out". We have a certain resource: we are born, we develop, then this resource ends, all sorts of minor damage accumulates. And along with the aging of various mechanisms, man and some animals age, after which they die. This is really a very sad picture, because if this is the case, then nothing can be done about it, because we cannot change human nature. To introduce some special super–protective systems into it is all out of the realm of fiction. But recently, more and more questions have begun to appear to this point of view.
Recently, scientists have been talking about the ongoing paradigm shift in the science of aging. There are more and more indications that we are aging for a reason, that we are really programmed to live healthy for a certain amount of time, and then some systems turn on in us, some turn off. In some way, a regulated process begins, the purpose of which is to bring us to the grave. So that we don't live too long and, at the same time, also grow old, that is, not too happily. This makes a lot of biological sense. And it seems to me that this harmful mechanism that starts and spoils us, it exists. And this is the cause of aging. And it sounds pretty grim. It turns out that almost biochemical suicide happens in us from the inside, but in fact, this is an extremely optimistic point of view. She is attractive precisely for her optimism. Why? Because if it is a mechanism, then it can be broken, and this is a much simpler, purely engineering task. You don't even need to know how something works to break something. It is enough to have some general ideas. And if we break this aging mechanism, maybe not completely, and it will work worse, and as a result, we will age more slowly or stop aging altogether. This is an extremely attractive point of view and hypothesis. Maybe it is incorrect, but it definitely needs to be checked.
– Have scientists already tried to break these aging mechanisms somehow?
– Probably the most sensible attempt is our project. We have stated from the very beginning that we will test this hypothesis – programmed aging – in order to break it. And we have been working on it for more than 10 years. Successes, maybe, could be more, maybe less, but it turns out rather than not.
Now there are several more scientific approaches. It is not always announced as a fight against the aging program. The first approaches began to appear, they reach the level of human testing. Almost ready for it.
– Could you tell us what these attempts are?
– There are several approaches. The first approach is not clear how it will work. They've been messing with it for quite some time. Success is variable, although there is something in this approach, of course. This is an attempt to influence the inflammation system in the human body, which is clearly in critical conditions and with age begins to behave differently than we need. Thus, it does more harm than good. I'm talking about the system of so-called innate immunity. And there are substances that are anti-inflammatory to one degree or another (which, in fact, is not quite true, these are substances that block part of the work of innate immunity systems, preventing it from damaging us too much). One line of research is connected with this.
Another line of research is trying to come from a completely different direction. With age, we accumulate so-called senescent (aged) cells. If you take the fate of a cell in the human body, or not necessarily a person, but some kind of multicellular, everything is a little tricky there. The cell lives, performs its own functions, and at a certain moment it must die. The process of programmed cell death is started, it is disassembled into its component parts, this is a very elegant, regulated and interesting process that ends with the cell disappearing. And a new one should appear instead (or it shouldn't). Not all cells behave so responsibly. Some "go crazy", declare that "we will begin to divide", roll back in differentiation, become undifferentiated cells similar to stem cells, begin to divide, the number of cells increases in this place and so a cancerous tumor appears. As we all understand, this is a very dangerous pathology.
There is a middle way: the cell does not divide, and does its job worse and worse, it seems to be aging. And with age, it seems that we have an increasing number of such aged cells. There is a separate technology that theoretically allows the targeted destruction of such old cells in the body. According to animal experiments, it turns out that if there are fewer such cells, then the animal feels better and, at the same time, gets younger. This is another approach to the fight against aging. By the way, he is quite close to us, because the way they move from a normal state to this decrepitude is clearly a programmed process. Some genes turn on, some turn off, but this can be controlled.
And finally, our approach. We believe that we are beginning to poison ourselves more strongly with special poisons. These poisons are called free radicals or reactive oxygen species. They are formed inside our cells, in mitochondria, in our power stations. What is very suspicious: the older we are, the more mitochondria of this poison form. We believe that this is not just so, but, indeed, it is programmed. You can also try to fight this. There are different approaches. We use a pharmacological approach. We synthesized a substance in this laboratory that gets inside the mitochondria with nanometer accuracy and does the only thing there – catches a free radical, prevents it from damaging the entire cell. This is a hypothesis, it has not been fully proven, but there are a lot of confirmations, and if this is true, then aging will work worse: we and animals that can be given this substance will live longer.
– Your drugs work on Skulachev ions. Is this exactly the mechanism you described?
– Skulachev ions are compounds that were invented in the mid-60s. With their help, it was proved that there is only one negatively charged place in our cells – mitochondria. We use them as a vector, a way to deliver what is needed, namely antioxidants inside the mitochondria. That is, Skulachev ions are positively charged particles to which a very strong antioxidant is chemically "sewn". This whole construction is called SKQ. If it touches anything living, any living cells with mitochondria, it accumulates a thousandfold in the mitochondria of living cells. This is the basis of our technology.
– Are your technologies tested on animals somehow? Could you tell us about the experiments, and on which animals they are carried out, on rats or on others?
– Our first experiments were carried out on isolated mitochondria, then on cells in culture, but quite quickly, more than 10 years ago, we switched to animal experiments. There were a lot of experiments. The substance has a very high penetrating power, so in most experiments we simply added a small amount of this substance to the drinking water of mice or rats on which we experimented. And then we looked at different things, for example, how long they live, at what rate they age, when they begin the period of old age, when they begin to die because of too much age. Sometimes we modeled certain age-dependent diseases on them. This is called animal models of diseases. They tried to cure these diseases or somehow stop their development. A lot of things have been done there. Basically, we worked on mice and rats. This is a standard laboratory facility, it is known to everyone. Their limitations are known – they do not model a person very well, after all, they are completely different animals. But we quickly discovered the effect of the substance on the eyes. In these animals, first of all, the aging of the eyes slowed down. They did not develop age-dependent eye diseases. That's what prompted us a little trick to get to the medicine, to the person, to clinical research, the most interesting thing for which we are doing all this. We started using the substance in the form of eye drops and then the veterinarians from the Moscow Veterinary Academy helped us a lot. They read our work and made a proposal to conduct clinical trials not on humans, but on their patients: pets. They were cats, dogs and horses. There was an absolutely wonderful effect, several age-dependent eye diseases were cured by veterinarians, under the guidance of Professor Larisa Fedorovna Sotnikova. And this, in fact, is a very romantic, wonderful part of our project, because here we were finally convinced that we should make medicine out of this thing. Rats differ from cats and horses very much and it worked for everyone. We thought that it should work on a person. And just 10 years ago, we launched a clinical program already with a trial in hospitals on volunteers – patients with various eye diseases. I won't name it so that it doesn't look like an advertisement, but many tests have been very successful. The drug was registered in Russia, and now we are at the final stage of testing the drug for eyes in the USA. Clinical trials are underway there now. If they are successful, then this will be the first case of a Russian drug approved in the United States.
– In 2016, an article was published about colonies of ageless mammals, African rodents – naked diggers. Please tell us about this study.
– In 2016, for the first time in Russia, a colony of absolutely amazing creatures appeared – small rodents the size of a mouse, called "naked diggers". This is an African rodent, it lives in the only place on Earth – in the Horn of Africa. But there are quite a lot of them there, it's not some rare species, but they are nowhere else. Whatever you take, they have everything special, it's just some kind of alien creatures, even though they are relatives of the mouse. Why are they very interesting to us? Because they live a very long time. If an ordinary mouse lives for 2-3 years, and three is a very good achievement, then how many naked diggers live, in fact, is not fully known. The experiment has been going on for more than 38 years, and the oldest digger, who was caught in Africa 38 years ago, is still alive. This experiment is not going on with us, but with American zoologists. The main part of the experiment is in the USA. We have long known about these amazing ageless and very long-lived creatures. A huge operation was carried out to get them for themselves. In 2016, the Berlin Zoo presented us with several colonies of naked diggers. They have been living with us ever since.
We are investigating them, trying to understand how they managed to "escape" from aging, because not only do they live a long time, but they do not "get worse" with age. They do not increase the probability of death, they do not increase the frequency of any diseases. A three-year-old or a 20-year-old digger is equally young. To understand the scale of what is happening – for a rodent 20 years, it's like 300 – 500 years for a human. This is an incredible longevity. One of the most important modern questions in biology is how they did it, what happened to them. We have been researching them for 5 years, and we have made some progress on this. If you want, I can tell you what kind of secret we found among the diggers.
– Yes, of course. Is it related to genes?
– Of course, longevity is related to their genes. Animals have nothing else, and since they all live so long, it's genetically programmed. It turned out that it seems to be a matter of fine-tuning these genes, because their genome is not much different from the genome of mice, and from you and me. We are close relatives – mammals. But mice live for two years. Naked diggers seem to live
30-40 years, and some medium-sized rodents, some guinea pigs, live for 8 years. How is it configured? With naked diggers, it seems to me, this is one of the most striking discoveries that have been made at Moscow State University in recent years – we managed to explain how they achieved this.
When we studied the work of the diggers' mitochondria, we accidentally found out a remarkable feature that their mitochondria are similar to the mitochondria of an embryo, not an adult organism. We took samples from 6-7 or even 15-year-old diggers, and their mitochondria still work like newborns. Further, if you look at them, they are most similar not to an adult rat or mouse, but to a newborn. They are also naked, they have no auricles, a large head and a small body. This is exactly a newborn baby rat. But the baby rat will be covered with fur in a few days and turn into a "normal" rat, will begin to age, and the digger remains in the state of a newborn, a child for decades, and children do not age. That explained everything.
Maybe he wasn't going to live long, maybe it wasn't some primary goal. Maybe he needed brain plasticity. But the digger stopped the animal's individual development program for its entire species at the child stage. Such cases are very rare, but they happen in biology. This is called neotenia – the preservation of infant or embryonic properties throughout life. The digger followed this path. I would guess why he needed it: this is a colonial animal, they live in "anthills" with a very complex social structure. The social structure of the mouse was not even close to the complexity of the diggers. For this, probably, very well-functioning brains were needed. It is known that in human children and young animals, the brain is the most plastic. And so they "froze" their development, leaving it in the cubs phase. And, maybe, "for change", quite by chance they got a long life, because their aging mechanism does not reach the point when it should start. It's not supposed to start in babies, but somewhere in the middle of life.
We published an article about this, probably in one of the best journals: Physiological reviews in 2017. In addition, it is a terribly fascinating biological fact, as you probably felt, an amazing biological story. This is still a very important result from the point of view of the fight against aging. This means that aging starts at some point, and this is a completely optional attribute of every animal. If some mechanism, some program is launched, then it can be found and broken. This fact proves the existence of a program disabled by the digger – the aging program, the fact that he once had it, and it was disabled, this means that something similar should happen to us, because the mechanisms of aging, at least in mammals, should be almost the same. Therefore, a naked digger is proof that we are looking for something that exists in principle. If he managed to turn it off in the process of evolution, perhaps we can develop some kind of technology to do it.
– The question is more of a philosophical plan: do you think a person really needs eternal youth?
– It seems to me that there is definitely a request, if not for eternal, but for a long youth. I think that no one wants to get old. This should not be confused with eternal life. It's not necessarily the same thing at all. There are a lot of animals that do not age, but their life is limited, they die quite quickly for various reasons programmed. Therefore, I do not see anything wrong with a person's youth lasting not up to 45 years, as is now officially recognized, but up to 90. Who will feel bad about it? What will happen next: whether we want to live more than 120, 130 years is a very big philosophical, social and psychological question. Maybe not everyone will want to, but I think it would be great to have such a choice. Not everyone likes to fly on airplanes, but we are all glad that there is such an opportunity. Therefore, I would say that we should give people this opportunity, and only then we will figure out who will use it and how.
– Is it possible to equate the word youth with the word health? It's just that basically, diseases accumulate in a person at a more mature age.
– Yes, of course, youth is health. In English, there is even such an expression "healthy life expectancy" – the duration of a healthy life. That's what I would call youth. And this should be increased. Unfortunately, with age, all our functions gradually weaken, eventually age-dependent diseases appear. That's why they are called that, because the probability of their appearance is much higher in old age. Simply because the period of healthy life allotted to you is over or is ending. Therefore, if we prolong youth, prolong a healthy period of life, then we postpone the time of the appearance of diseases, or maybe they will not appear at all.
– Do you think humanity needs to expect some kind of magic pill to continue its youth, or it can somehow prolong its youth on its own, for example, with the help of a healthy diet or a healthy lifestyle in general.
– Aging is clearly a regulated process. Someone ages faster, someone slower. There are many ways to accelerate your aging: poor nutrition, alcohol, smoking… In fact, improper social behavior also leads to premature aging: living in isolation, lack of social contacts… According to statistics, such people live less. And they don't just live less, they have all sorts of age-related sores earlier. Therefore, until scientists have developed a "pill for old age", at least you can not accelerate your aging. This will help a lot.
To do this, the very first recommendation is a healthy lifestyle and another of the well–known set of recommendations, but in addition, if we assume that aging is a regulated biological process, then we need to take into account that a person is a very social animal. According to statistics, people who feel needed by other people live for a long time. This is very clearly seen by, for example, teachers at universities. I would not take teachers in schools as an example, because it is a terrible stress to work with these "ragamuffins and tomboys". It's very hard. And teaching at universities is less stressful work, and, of course, no less important. From year to year, every day you come to a certain "cave" from the point of view of the biological program, your "tribesmen" younger than you gather there and open their mouths to listen to what you broadcast to them. You somehow manage them, control the situation. You are clearly very much needed. It seems to me that this should give some biochemical physiological signals, they, of course, come from the brain, which regulates everything. These signals, after all, should slow down the aging program. Because, for some reason, you are important to your species, and this is the most important thing from the animal's point of view. You should be needed by your relatives. Such people should not age so quickly… This is evident from the professors, who can often "drive the whole department around the neck" until they are 90 years old. Everyone works for them: graduate students, employees, and then he retires, often not because he can no longer, but because it's just accepted. And a person "burns out" in a few years, having lost some kind of core in life. And what does "burned out" mean, what does it mean lost the rod? This means there must be some kind of regulation, it must be arranged somehow.
Now there is a very unique motivation to live more: you can live to develop a cure for old age. There is nothing more stupid than to grow old irreversibly a few years before the appearance of this drug. Right?
And if someone is thinking about it, then now, at least, it would be very smart not to accelerate their aging. Think about your health and think about the lifestyle that you lead. Not only in terms of sports and nutrition, but also communication with other people.
– How do you expect the pace of development of science in the field of combating aging?
If everything develops in the direction it is developing now, interest in the field of combating aging will increase, companies, money, technologies, scientists will come here. While it's still at the very, very start. We spend criminally little resources on the fight against old age. But at least we have already started moving in this direction. If this continues to develop, then I think that in the next five to ten years the first technologies will appear that can really do something: drugs for pharmacological intervention, some other techniques. It seems to me that it is quite possible to double your youth. I am 47 years old, I do not know if I will make it, although I really hope for it, but my children (the eldest is 17) are in the group that can definitely get it. Maybe they will help to do all this.
I cannot say how much this will increase a person's overall life expectancy, because if we think about it, a person has already dramatically increased his life expectancy many times. She barely reached the age of 30 while we were running through the jungle. Then we defeated hunger, cold and predators with the help of fire, skins, weapons and agriculture. Life expectancy was almost doubled. People began to live up to 50-60 en masse. Then bacterial infectious diseases "got out", they sharply limited the average life expectancy of mankind until the middle of the 20th century. Then antibiotics, sanitation, hygiene, and clean aseptic operations were invented. And we have what we have: it turns out that a person can safely live up to 80 and 90 years. And it turns out that cardiovascular diseases, cancer, neurodegenerative diseases, which were very rare, back in the 18th and 19th century, no one had lived up to them yet. There were, of course, units. Centenarians have always lived, but it was a kind of exotic. And if you had "caught" a doctor in 1900 and said that Alzheimer's disease would become a mass disease, he would have laughed in your face. This is a disease after 70, 80 years, where will you find so many people of this age in those years?
Therefore, humanity has pushed this boundary many times due to progress in medicine. I think if we now learn to interfere with the very essence of aging, until the first technologies clearly will not work at 100%. We'll push back some more. And something we don't know about may come out there. I'm afraid it will be some kind of psychology... will a person want to live after a hundred years? Will he be involved in society? There will probably already be some gadgets flying around all of us, and elderly people simply will not want and will not be able to master them all, and without them social life will be impossible… Some kind of restriction may come out, completely stupid, which we simply do not know about. Therefore, I would be very careful in making forecasts for the extension of the overall life expectancy, but we would have to deal with the period of youth… No one seems to object to this, and it is more or less clear how to do it.
– There is such a direction as biohacking. Are you familiar with this direction and can you comment on it somehow?
– Yes, perhaps our project even somehow contributed to the emergence of biohacking, because our main principle is hacking the aging program, which is why we are such "biological hackers". Our supervisor Vladimir Petrovich Skulachev, my father, has been talking about this since 2005. At some point it became popular. There are people who say that we will not wait for all these neat double-blind placebo-controlled clinical trials from pharmaceutical development companies: "We will get ourselves a set of certain drugs, dietary supplements and something else to use it all, because for general scientific reasons, it should slow down aging." In fact, here, of course, "everything is in a mess": there are some rather proven scientific concepts on which they rely, and rather bold hypotheses. As a result, I have a rather negative attitude to this, because this is my professional field. I am a drug developer, I professionally prove that the medicine works or not. I know how difficult it is to do this. How many false results there are here, when you really want something to work, it will work. Moreover, it even works on animals. When you test a drug on animals, it is very important that the laboratory assistant who adds the substance to the drinking bowl, so that he does not know where the substance is and where the dummy is. It would seem that rats cannot know this, but nevertheless, the laboratory assistant knows it. And he always loves the experienced group more than the control group, and they, of course, feel it. Therefore, experienced groups always live longer. You can give mice any substance, and it will prolong their life if the experiment is wrong.
Therefore, of course, biohacking is, of course, unprofessional, a kind of amateur attitude to a very complex field – pharmaceuticals. Biohackers are great fellows that they believe that it can be done. The general movement, the general message, it is very correct. Aging can and should be fought. And they are great for making a fuss in this area, because humanity is engaged in anything, except what we will all eventually die from. How much money we have recently spent on new weapons to kill each other, about which everyone knows that it will never be used, it is done so, for a "tick". And how much money has been spent on research on aging? Probably, the ratio is 1 to a million or to hundreds of thousands. And what is more important? You can arm yourself to the teeth, sit behind a stone wall and hold the defense, but you will die of aging, because you forgot to develop a weapon from this enemy. That is, this is outright stupidity. And a very big "message" of biohackers, enthusiasts is that: "Guys, what are you doing? You're doing something stupid. We need to finally get together and get smart." In this sense, they are great fellows, but the specific recommendations they give are either not proven, and sometimes even a little funny.
– Maxim Vladimirovich, maybe we will sum up some of our conversation on a more positive note. Would you like to wish something to our viewers and readers?
– I would like to wish all our viewers and readers not only to live longer, but to live longer young and healthy. Now it is very important from different sides. The most important step to prolonging your own youth is to think. Brains are generally useful to use. Think about how you live, what you eat, what kind of lifestyle you have, what kind of people you contact and how. Try to bring some positive into all the components of your life. From the point of view of general biology, from this you should live longer and keep your youth longer. Therefore, please pay attention to yourself and your life. This is an absolute value. And who, if not biologists, know about it?
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