What scientists are doing to prolong our life and youth

How to Beat Aging

Andrey Konstantinov, "Russian Reporter" No. 25-26/2014

Eternal youth, victory over aging, elimination of causes of death… All this sounds like words from a fairy tale or from a science fiction story. Meanwhile, quite serious people are engaged in the fight against the aging of the human body – doctors of sciences, professors, Nobel laureates. The journalist of "PP" visited the international conference "Genetics of aging and longevity" and assessed the prospects for prolonging our lives

Sochi. We are the only residents of the Olympic Village abandoned by people after the Games. The sea was fenced off from the coastline with an impassable fence (probably in case the terrorists get out of the depths of the sea), but it does not pull to the beach. Here I want only one thing – to listen again and again and ask the audience how to prolong our young years.

Who, if not them, should know this – 200 scientists from 31 countries gathered at the conference "Genetics of Aging and Longevity", who devoted themselves to studying aging, trying to slow it down, and if possible, stop it and even reverse it. It turns out that they do it well: simple organisms like yeast and worms have learned to prolong life 10 times.

With laboratory mice, who are always the first to try what a person will have to do later, success is much more modest: their life can only be extended twice so far. However, if my life was extended twice, I would call this achievement not modest, but the greatest in history. But in humans, everything is much more complicated – at first, many years of preclinical preparation of therapy, then no less lengthy clinical trials.

Are we going to be the last generation destined to die before even a measly hundred years? Or is there still a chance?

How nature does itThere is a round table.

–Aging is the development of endogenous pathologies in late life, which increases with time," David Gems from the Institute of Healthy Aging at University College London coined the definition.

Other participants have their own definitions, no worse, but no one disputes that aging is a pathology, not the norm. There is no healthy aging. Not so long ago, there was no such unanimity.

"The only reason people are trying to find something positive about aging is desperation," says Jan Weig of the Albert Einstein College of Medicine and breaks into applause.

A dispute begins about the main mechanisms of aging. It seems to be clear that Darwin and his evolutionary theory are to blame for everything. The variability of species is accelerated as a result of the rapid change of generations, evolution is beneficial. It is not clear exactly what mechanism triggers aging. Maybe it's a simple accumulation of errors in the body? But up to a certain point, breakdowns are successfully repaired, cells are renewed, and the life expectancy of different species varies too widely.

Maybe there is a program of slow suicide? "We carry the seeds of death within us," said the evolutionist August Weisman, who put forward this hypothesis. Or maybe we are getting old and dying from the work of the same mechanisms that provided us with growth and development in our youth? It's just that evolution didn't take care to turn them off in time, and they start working for destruction.

– For me, the key question is not so much what aging is, but how nature regulates life expectancy in general, – Vadim Gladyshev, a professor at Harvard University Medical School, explains to me. – After all, the life span of different animals is not the same, from a few days to several centuries. The shrew and the whale are mammals, have a common ancestor, but the shrew lives for a year, and the whale lives for more than 200 years. It is believed that the life expectancy of mammals is related to the rate of maturation of the body and body weight. The larger the mass, the longer the body lives. But the mouse and the naked digger are about the same size, while the digger manages to live 10 times longer than the mouse – more than 30 years. We are trying to study such pairs of species that are as close to each other evolutionarily as possible. For example, an ordinary bat and Brandt's moth – this one of them is found, including in Russia, and has lived for more than 40 years, at least not less.

In the world of anti-aging fighters, Gladyshev became famous for deciphering and being the first to investigate the genomes of two major celebrities: the naked digger and Brandt's moth.

– The moth is one of the smallest mammals, weighing about 4-8 grams. And at the same time it flies, which is generally unique in terms of life expectancy, because a huge amount of resources is spent during flight. How does nature do this? How can we do the same? We studied her genome and found two surprising changes. One is a growth hormone receptor, the second is an insulin factor receptor. These two genes are very well known in connection with the study of aging. If you affect these areas, turn them off, then the organisms become smaller and live longer. A mouse that had the growth hormone receptor gene blocked became dwarfed, but lived twice as long.

Such different centenariansI want to move from long-lived animals to people.

Moreover, Claudio Franceschi, Professor of the University of Bologna, almost the world's leading expert on longevity, came to the conference. Claudio is one of the leading researchers in the project "Genetics of Healthy Aging in Europe". We started talking after the report – he said that human health is determined not by one, but by three genomes: bacterial (the one that microbes living in our body have), nuclear and mitochondrial.

– Centenarians are a positive topic, even though it's about aging. But they are not easy to meet: only one out of four or five thousand people lives to be a hundred years old. It is easier to study centenarians in Italy, because there are many of them – 15 thousand. As in Japan, for some reason people live there more than in all other countries. Thanks to this, we are now studying not only centenarians, but also super–centenarians - those who are over 110 years old.

– And how do they differ from ordinary people?

– The most noticeable and surprising difference is that these people live thirty to forty years longer than the rest, and most of them have avoided the main diseases associated with aging, such as diabetes, cardiovascular diseases, dementia. And even if they get sick, it's much later, for twenty or thirty years. Half of them have good intellectual functions, that is, they can live independently. Of course, most of them are women. And their already aged children are also in much better shape than their 70-year-old peers born to ordinary parents. Generally speaking, if you had centenarians in your family, the chances of living to a hundred years increase dramatically.

– Do the centenarians of different countries differ from each other?

– Yes, centenarian Italians are unlike centenarian people in Japan or Russia. They have different genetics and different living conditions. By the way, it would be very interesting to study Russian centenarians. But even in one country there are completely different groups: for example, in the north of Italy, the ratio between centenarian women and men is seven to one in favor of women. But in Sardinia, in the province of Nuoro, where I conducted research, the ratio is different – one to one. Sardinians are generally strange people, their genome is noticeably different from the usual for Italians, but their culture and whole lifestyle are also completely different. I'm thinking about moving to Sardinia.

– How do you study people who have survived the centennial anniversary?

– We collect their DNA, feces, urine, study the genome and its activity, and in the feces we study the genomes of all bacteria from their intestines. Aging is a very complex process, but thanks to the huge amount of information collected, we have already found several genetic "markers" of longevity.

– Do they have any special genes?

– The longer a person lives after 80 years, the more it is the merit of genes. Centenarians have, for example, special protective genes, that is, protectors that prevent the development of age-related diseases. Just this week, an article was published in which we characterized one of them – a cardioprotector that protects against cardiovascular diseases. But it is important not only the presence of certain genes, but also their activity, which proteins and fats are present in different parts of the body.

– At the level of physiology, did you find any differences between centenarians and other people?

– Here is one of the discoveries I made. I took lymphocytes, immune cells of centenarians, and found that, unlike lymphocytes of other people, in the absence of nutrients, they begin to eat other cells, becoming "cannibals" in order to survive. A similar phenomenon can be observed in cancer: this is how cancer cells behave.

– Why did you study lymphocytes specifically?

– Generally speaking, I am an immunologist. And my main idea is that inflammatory processes play a huge role in aging. You start producing more and more garbage, more and more damaged cells and damage signals. These signals activate the immune system – the inflammatory process is stimulated, which generates the main diseases associated with aging. My hypothesis of aging as a chronic inflammation, which only gets worse over time, has now become very popular.

– It turns out that if the immune system is to blame for everything, which causes inflammation, the immunity should not be increased, but reduced?

– In general, yes. That is why substances such as aspirin or the immunosuppressant rapamycin, under certain conditions, show themselves to be quite promising "medicines for old age", suppressing inflammation.

I continue to talk with Claudio Franceschi. The topic is delicate: microorganisms living in us. The main way to study them is fecal analysis.

– It turned out that centenarian people really have important differences in the microbiota, concerning, for example, the energy supply of the body. The bacteria that inhabit our body have a hundred times more genes than we have ourselves, and some of them seem to play an important role in longevity," an Italian professor explains to me.

– Is there any way to improve the state of your microflora?

– Now it has become possible to transplant the microbiota of one person to another. In this way, some inflammatory bowel diseases can be cured, or, on the contrary, they can be infected with obesity, as has been shown in mice. But we must remember that the microbiome is one of the most complex ecosystems in the universe, it contains at least 300 thousand species of bacteria that produce vitamins and poisons, extract energy for us from food. Their importance is usually underestimated, and they are very important.

– So, is it time to do a long-lived fecal transplant for yourself?

– No, wait, we still need to study this question. It may be more effective to transplant the microbiota of young people to the elderly. So far, I have collected data on all the genes of all the bacteria present in the feces of centenarian people. But the transplant is not done once and for all. It will have to be repeated regularly all our lives, because we have a tendency to maintain our own, unique microbiota.

Let's move on to the most urgent. How to live in order to stay healthy longer. Thousands of books and pamphlets have been written on this topic. But there is still no final clarity in science.

– We have come to understand that aging begins in the mother's womb. What you will be like in 70-80 years is the result of all your previous life, all the experience of your immune system. It is important, for example, what you ate when you were a child, starting from the first year of life. We have a large project to study the nutrition of centenarians, and we have seen the important role of the Mediterranean diet in combination with physical activity. The Mediterranean diet is olive oil, fish, fruit and lots of water. Especially elderly people should drink a lot of water: their body is prone to fluid loss, which is very bad for the heart, and not only for it. It is also important for the rest to drink two liters of water a day – well, your climate is cold, maybe a little less for you. But still, please drink water. Not vodka!

– Well, is a glass of wine a day useful?

– Two is better! Wine is a good thing if you don't drink it in liters. It is also very good to add vitamin D and folic acid to the Mediterranean diet, especially in old age.

– But you yourself said that all people are different: a diet that is good for Italians may not suit Russians.

– It suited the Poles – we studied 1,250 Poles, five groups living in five different places: in Warsaw, the Polish province, Italy, Great Britain and the Netherlands. Can you imagine what it's like to convince so many Poles to switch to a Mediterranean diet? You can't, but believe me, it's very difficult. We convinced them to live like this for exactly a year, and then conducted research – the picture of changes was positive, there is also an article about this in Nature.

– What do you think, will people be able to win or significantly postpone old age in the coming decades?

– I have been studying aging for a quarter of a century, and I have the impression that we have only scratched the surface. We need time, it's a very difficult problem. A lot of disparate facts have been accumulated, but there are not enough unifying concepts. As a colleague told me this morning, there are at least 50 ways to live to be a hundred. I will say more: every centenarian has found his own, somewhat unique way.

Planet of the ElderlyMeanwhile, the conference continues.

– Thanks to the development of medicine and improving the quality of life, the proportion of people over sixty years of age will constantly increase. If nothing is done, it will be a disaster even from an economic point of view," says Brian Kennedy, director of the California Buck Institute.

People over 65 are the fastest growing age group in the United States, according to UN forecasts in some developed countries in 20 years they will make up about a third of the entire adult population. There is only one way out: to make the elderly healthy and active. Governments, corporations, and public organizations advocate for this, but for some reason no one has money for research. Our conference was organized by the private charity foundation "Science for Life Extension". Its head, Mikhail Batin, has been financing, organizing and finding money for research aimed at combating aging with rare stubbornness for many years.

– The main cause of people's suffering is old age and death, – he convinces with the energy of an evangelist. – But science brings good news: human aging can be slowed down. That's just one message is not enough – we still need to do something to make it come true! In the field of scientific research on life extension, only a thousandth of what would be worth doing is being done. Meanwhile, radical life extension is now a solved technical problem, like a flight into space after Tsiolkovsky's work.

Old age is like a fake melodyAmong the scientists at the conference there are many Russian professors working at the best universities in the world, mainly in the USA.

It's like being present at a meeting of a secret society of progressors, whose members serve a common purpose in different parts of the world. They gathered in Sochi largely thanks to the efforts of the conference program director Alexey Moskalev, head of the Laboratory of Genetics of Life Expectancy and Aging at MIPT.

– Is it possible to say that you are struggling with aging?

– I'm more of a researcher, an observer of nature, not a fighter. But to fight aging, you need to have a weapon, and I am one of those who creates it. We can say that our weapon is a scientific method.

– What is aging from the point of view of modern science?

– If you ask a biologist what life is, he will probably get confused in words. This is about the same with aging, although there is, of course, a classic definition from textbooks that aging is a progressive decrease in the viability of the body with age. Scientists are trying to identify criteria that allow us to judge the degree of aging regardless of age – for example, by the amount of DNA damage. If we list these criteria, it seems that aging is a set of completely different processes occurring at different levels of the organization of living matter: molecular, cellular, at the level of cellular interactions, at the level of functional systems such as respiratory or circulatory.

– For example?

– For example, with age, more and more cells lose their ability to divide, tissue regeneration is disrupted. Some cells switch to a suicide program. Evolution has provided that if the DNA is severely damaged, a program of self-destruction of the cell is launched so that its descendants will not be reborn into a cancerous tumor. Communication between cells is also disrupted. If a cell receives the wrong signals, it either starts dividing rapidly, or stops dividing, or gives rise to the wrong type of cells. And at the level of the circulatory system, changes such as thrombosis, atherosclerosis, blood supply to the heart muscles, brain, strokes, heart attacks are already occurring.

– It turns out that these are some kind of disparate processes, but something unites them, right?

– We can say that the main thing in aging is a violation of the internal balance in the living system, when self–regulation mechanisms break down, which normally compensate and repair all malfunctions in the body. The DNA of the cell, its "brain center", is damaged, errors accumulate in it. Cells send each other the wrong chemical signals, the enzymes that regulate the activity of genes stop working correctly. DNA is such a piano, and enzymes, as it were, play music on this piano – this is how the life of the cell proceeds. But as we age, the melody turns out to be more and more false.

– And what exactly do you do?

– I study the effect of stressful factors, such as radiation, on life expectancy. I was able to show that radiation in small doses does not decrease, but increases life expectancy. This does not mean that everyone needs to run to be irradiated. Playing with radiation is not worth it, it is unpredictable even in small doses, can lead to cancer.

– And what is this mechanism?

– I was able to show that, most likely, a small dose of radiation leads to the selection of cells resistant to radiation. And these are the very cells that will be resistant to other stress factors. They will age slowly, and the whole body will age more slowly. Then I began to try other stressful factors, and it turned out that moderate short-term overloads prolong life. For example, exposure to high or low temperatures encourages cells to recover after damage. And most importantly, if the stress was moderate, the system not only successfully recovers, but also moves to a higher level of protection. It's like hardening. It is easy for some organisms to extend their life expectancy by limiting the caloric intake or exposing them to regular temperature influences – this is how we turn on the mechanism of stress control.

– Long-livers often drink and smoke quite to themselves – is this also about moderate stress?

– There are lucky people, owners of successful genes, who can live up to a hundred years without leading a healthy lifestyle, simply because their stress-fighting enzymes work better. This is a phenomenon of family longevity, passed down from generation to generation. But this does not concern most of humanity.

– Genes – sounds like a sentence.

– Only until gene therapy really got on its feet. For example, we are very interested in stress–resistant animals - such amazing centenarians as the naked digger and Brandt's moth, gray and bowhead whales. We study their genomes to use this knowledge to create new drugs. Someday their stress-resistance genes in the form of additional copies will be embedded in the human genome and prolong our lives. This year, the Chinese made a virus that injected mice with one of these genes, and their life expectancy increased by 20%.

– What funds should we hope for in the near future?

– According to one of the main models, aging is a chronic inflammatory process. And some of the most promising drugs are now considered to counteract inflammatory processes. But the problem is not only in inflammation – there are different, relatively independent mechanisms of aging. Therefore, we started looking for combinations so that one substance affects one mechanism, another on another, and indeed, sometimes we manage to achieve a more pronounced effect of slowing down aging.

 – I've been asking various researchers if they themselves take any "medicines for old age". I have already been called rapamycin, metformin, small doses of soluble aspirin, melatonin. How do you feel about this?

– All these substances can have serious side effects. For example, aspirin is not suitable for me: asthmatic syndrome develops. And as for melatonin, it is known for sure that in some people it can cause tumor formations. Therefore, for now I am limited to gormetins – substances that stimulate stress resistance. They are found in green tea, turmeric, in some berries, fruits, herbs.

– That is, you just consume certain products.

– Yes, and besides, I know which products need to be restricted. There are a large number of experimental studies showing that excess methionine reduces life expectancy. And these are red meat, tuna, egg, milk, rice. I also switched from sunflower oil to olive oil: there are fewer polyunsaturated fatty acids.

– How do you feel about fasting? For some animals, calorie restriction allows you to live longer.

– The effects of fasting are largely due to the fact that an overeating person restricts the use of foods that are not that useful anyway. By itself, fasting does not prolong people's lives.

– How important is sleep mode? For example, I often go to bed closer to three or four in the morning, all the time somehow goes out by itself. Is it harmful?

– Most likely, yes. The peak of the release of the hormone melatonin is reached somewhere at eleven in the evening, and if you sit out this time, then it will be difficult for you to fall asleep for the next two hours. Then a new peak, and so every two hours. If you do not sleep at this time, desynchronization of internal rhythms occurs. When you sleep, stem cells come out of their niches and start looking for damaged areas of your body – where things need to be regenerated. This happens only during sleep. Sleep rhythms are very important, but with aging they are destroyed, and perhaps this is one of the causes of aging diseases. Therefore, artificially destroying your rhythms, you can accelerate aging. But this topic has not been sufficiently studied yet.

– How do psychological factors affect the rate of aging?

– The hormonal background largely depends on our mood. For example, stress hormones such as cortisol play a very important role in aging: they cause diabetes mellitus, atherosclerosis. If we constantly keep cortisol at a high level, then, in fact, we simulate the processes of accelerated aging.

– You are struggling with aging as a scientist, and we, ordinary people, can somehow help you with this?

– It is very important to create a public opinion that aging is abnormal, that it can and should be eliminated. Public opinion influences decision makers on which areas of science to fund.

A question of focusThe fifth day of the conference, I'm about to fly away, but I can't tear myself away from the reports.

In Moscow, the usual objections of friends are waiting for me. From one flank is most often heard: "But if they learn to prolong life, then Putin is forever!" For some reason, people care about their own fate much less. From the other is heard: "God intended us not to be like this, man has his due date." And from both flanks a friendly chorus: "What about overpopulation? After all, if people live for a long time, there will be no place left." You might think overpopulation is the main Russian problem.

I finally leave the conference venue, but in the corridor I meet Pyotr Fedichev, head of the Laboratory of Systems Biology of the MIPT pharmaceutical cluster, scientific director of Quantum Pharmaceuticals. This is exactly the person who is engaged in the development and introduction of new "anti-aging" drugs to the market. Fedichev, as always, is surrounded by a team of guys, buried in computers, wherever they are.

– What are they doing?

– Analyze data on various age-dependent genomes to find effective markers of aging. We can't give a person a pill and wait fifty years to see how it will slow down aging. In order to shorten the period of clinical trials, we need to find markers that would show in a short time how a particular drug affected the aging process. I think this problem will be solved pretty quickly: such things always depend on practical necessity. As soon as humanity really wants to start testing life-prolonging drugs, a lot of smart people will get together and make a normal biomarker.

– Aren't people now engaged in the creation of such drugs with might and main?

– You see, no matter what practice a person follows – a health improvement system, diet or gymnastics – he will not live even to one hundred and fifty years. All we can try to do is push our deadline from sixty to a hundred. At our company, we conditionally differentiate all potential medicines into strong and weak protectors. Those that are weak improve your condition within this forty-year interval when everyone is getting old. We try not to deal with them.

- why? After all, this is also not bad…

– These types of therapies do not work to dramatically prolong healthy longevity, but rather to slow down the aging regime. But a world in which old age lasts twenty years longer will not be able to support itself purely economically. Pension systems in many countries are already bursting at the seams. The number of visits to the doctor is growing rapidly with age, as well as the cost of treatment, while people stop working. The last year of a person's life in developed countries now accounts for the same expenses as for his entire previous life, and the result is negligible. The only practical way is to turn off the aging mode so that medical costs stop growing with age, and the person remains productive.

– When else will we be able to turn it off… It would be necessary to reach this somehow. To begin with, it would be nice to live for a hundred years on weak geroprotectors.

– It seems to me that this is primarily a question of focus of efforts. If the whale and the digger, our close relatives-mammals, managed to switch the aging mode, then for humans this is an engineering task that must be solved. It is necessary that a sufficient number of intelligent people understand that a significant extension of life is possible. And then we thought about it and did it. It is likely that there is already a preclinical drug that seriously changes the life expectancy of mammals – at least some of the reports at the conference gave me such hope.

Portal "Eternal youth" http://vechnayamolodost.ru02.07.2014