Gerontologists are ready for a breakthrough
Stop, aging!
Elena Kudryavtseva, "Ogonyok"
Leading scientists from 17 countries came to Russia to solve the problem of aging. It is now, in their opinion, that a critical amount of information has been accumulated that will help to find a medicine that seriously prolongs a person's life
A cure for old age will be found within the next ten years. However, they will most likely treat pets first. And men taking new drugs will have to turn into women – at least at the level of the genes...
These are just some of the theses listed by scientists at the conference "Ways to achieve active longevity" held in Kazan at the end of April. The most famous scientists engaged in the problem of life extension gathered here for four days from all over the world. Geneticists and gerontologists, biologists and pharmacologists, genetic engineers and immunologists – about five hundred scientists in total – said that for a breakthrough in stopping aging, it is necessary to combine the efforts of specialists in all fields. The conference was organized by the biotech company "Initium Pharm", the Investment Development Agency of the Republic of Tatarstan and the Institute of Biology of Komi NC UrO RAS.
– When I started to deal with the problem of aging, each biologist had his own view on this process and everyone did something different, - Michal Yazvinsky from Tulane University (USA) told Ogonka.– Then there was a breakthrough in genetics: during experiments on animals, we saw that changing the activity of specific genes can radically prolong life. Since then, we have found many ways to prolong life – including with the help of pharmaceuticals. And now we need a holistic integrated aging system that would show how changes at one level of the body respond to another.
Scientists recognize: they do not fully know what aging is and what to consider its beginning. Is aging the cause of age–related diseases such as cancer or Alzheimer's disease, or, conversely, various diseases, "overlapping" with each other, eventually give rise to old age - the gradual extinction of body functions?
– This is a very important question that we cannot answer yet, – says Professor Jan Weig from the Albert Einstein College of Medicine (USA).– It is known that the potential of the human body is much greater than what we see. I think within ten years we will be able to develop mechanisms to intervene and stop aging. We are faced with the task of extending a person's life to 115, 120 or 200 years. And this is not a question of pessimism or optimism – it is a question of accumulating scientific knowledge.
Everything is like whales
"It is important to understand what aging is and where the beginning of this process is, because only in this way we will understand what is the main target for a possible drug," a professor at Harvard Medical School (USA) explained to Ogonka Vadim Gladyshev.
Professor Gladyshev has been engaged in comparative studies of the biology of mammalian longevity for many years. It was in his laboratory that the genome of the mysteriously long–living animal of the naked digger, giant long-lived bowhead whales and tiny Brandt's bat (a joint project with the Institute of Biology of the Komi National Research Center of the Ural Branch of the Russian Academy of Sciences) was first studied - it lives many times longer than its relatives, about 40 years. By the way, last year Professor Gladyshev received a mega-grant from the Government of the Russian Federation to create a laboratory for the study of aging at Moscow State University.
The study of long–lived animals at various levels is a fashionable trend of modern science. Scientists are trying to understand why different creatures, especially mammals, which once had a common ancestor, acquired such different life spans in the course of evolution. The answer, in principle, is: because the same genes work differently in different creatures. At the same time, in long-lived mammals, the gene activity profile is similar, despite the fact that, say, in the kidneys, liver, brain, it differs.
Most likely, this means that there will be no "universal" pill for old age – different mechanisms of longevity will have to be activated in different tissues and organs.
The works of Vadim Gladyshev and corresponding member of the Russian Academy of Sciences Alexey Moskalev (he was the co-chair of the conference) proved that the key to longevity is the same for a variety of creatures: they learned to survive in conditions of oxygen deficiency (hypoxia). This science is perfectly mastered by an underground naked digger, and whales that go under water for a long time, and Brandt's bats that slow down breathing in a dream. To understand how the body "learned" to exist in such conditions is especially important for people, because hypoxia causes accelerated aging in humans: without enough oxygen, all organs and tissues suffer, primarily the brain. And the older a person is, the worse his brain is supplied with blood and the more destructive it is manifested at all levels of the body.
Therefore, scientists urge to protect the vessels that supply the brain with oxygen. This is best facilitated by regular swimming, olive oil, herbs and berries in the diet – such a diet contains vitamin K and polyphenols, which are indispensable here.
Italian recipe
Interestingly, many variants of genes, which are commonly called genes of centenarians, make it possible to tolerate various kinds of stress well. This was told at the conference by one of the most cited gerontologists in the world, researcher of centenarians Claudio Franceschi. He deciphered the genomes of several thousand Italians who have crossed the 90-year milestone. Moreover, he examined not only the DNA of centenarians directly, but also the genome of bacteria living in their intestines (the human genome, by the way, is about 25 thousand genes, and the genome of microbes is more than 10 million). As a result, it turned out that, from the point of view of genes, centenarians are such naked diggers and bowhead whales among us. They have all the same genes as other people, but some of their genes work differently, explains Professor Yusin Su, a researcher of genetics of 100-year-olds from the Einstein College of Medicine. According to her, special gene variants protect the "lucky ones" from various adverse environmental influences. Moreover, such people can indulge in harmful excesses, for example, smoking until old age, because they are genetically predestined to overcome adverse environmental factors better than others.
In turn, Gil Atzmon (University of Haifa, Israel) found that longevity has a pronounced hereditary component. So, it is generally believed that genes usually affect life expectancy by 25%, and lifestyle – by 75%. But even the most correct way of life allows you to live on average about 85 years. Centenarians often do not differ in the right way of life, but they live for more than 90, 100, or even 110 years. Therefore, the contribution of heredity to their longevity is up to 50%.
What should everyone do who didn't get the centenarian genome? We should start by not panicking. It has been proven that if a person reduces the calorie content of food by 20-30 percent, switches to a healthy diet – for example, a Mediterranean diet with an abundance of fish, greens, vegetables and olive oil, limits alcohol, quits smoking, regularly (but without fanaticism) exercises and gets enough sleep, then most likely he will live 80-90 years. But this is not the modern demand of society: a person wants to lie on the couch, eat fried pork and potatoes and at the same time live 100 years thanks to a magic pill. This is a real challenge to medicine. And she's trying to answer it.
The "virus" of old age
There are already several classes of drugs that claim to be a cure for old age. The class depends on what, from the researcher's point of view, "triggers" aging, or a cascade of fading functions. For example, one of the theories says that old age is almost a virus and it needs to be treated with antiviral drugs.
We are talking about the so–called mobile genetic elements - these are special jumping genes that really spontaneously "jump" throughout the genome, arbitrarily embedding themselves in any place of DNA. Now scientists are studying them in the context of the molecular mechanisms of aging. It turned out that they can multiply like viruses inside the genome of an aging cell, causing chromosome breakdowns, unplanned shutdown of some and inclusion of other genes. It is noteworthy that in the course of evolution, reproduction in the genome of this egoistic DNA played a key role in the emergence of mammals, primates and even humans as a species. But today the activation of these "nomadic" genes leads not only to cellular aging, but also to oncological processes. Scientists are developing drugs that in the future will slow down aging with the help of anti–retroviral drugs - like those that are used today to suppress HIV or gene therapy.
Another theory (developed by Professor Franceschi) says that aging develops against the background of chronic inflammation. With age, the immune system works worse and cannot completely suppress inflammatory processes. And it is because of this that most age-related diseases develop, including atherosclerosis, cardiovascular, type II diabetes, oncology and the new scourge of the 21st century - Alzheimer's disease.
It is the aging of the brain that is increasingly attracting researchers who are sure that suppressing inflammation is the key to a clear mind for many years.
The fact is that the brain for the most part consists of non-dividing cells. And at the same time, it consumes most of the oxygen and glucose in the body. As a result, a kind of "waste" of production accumulates in the brain in the form of unprocessed parts of cells. Therefore, for the prevention of aging of the brain, it is important that the processes of gradual self-digestion of garbage cells regularly take place in it. This is facilitated, for example, by periodic short fasts and certain substances, including spermidine, which is abundant in broccoli sprouts, legumes and cereals. In clinical studies, it has shown itself to be a geroprotector (a substance that stops aging, which improves memory).
According to Professor Moskalev, neuroinflammation is one of the causes of not only Alzheimer's and Parkinson's diseases, but also senile depression. Therefore, it is important to use a special anti-inflammatory diet for prevention. In fact, it is closer to vegetarian and includes a lot of vegetables, whole grains, legumes and fruits. With age, the number of omega-3 fatty acids in the membranes of brain cells decreases, which have an anti-inflammatory effect, and they need to be replenished by eating fatty fish and linseed oil. Also, galactose (it contains a large amount of whole milk and ice cream) and fructose (sweet fruits, sweeteners in store food) do not affect the brain very well.
Does this mean that it is necessary to treat old age with anti-inflammatory drugs? In fact, yes (gerontologists themselves often take aspirin and ibuprofen in short courses), but it is even more reliable to prevent inflammation – say, maintaining a healthy background in the intestine. Useful microflora creates vitamins, amino acids, bioactive substances for us, but in return "requires" a sufficient amount of prebiotics (dietary fiber) – these are substances that we do not digest, but the intestinal microflora consumes them.
– The way of eating is not just a diet and the amount of calories consumed, – says Claudio Franceschi.– By changing it, we change the microbiota– the community of bacteria in the intestine - and thereby literally switch your body to another aging strategy. Today it is clear that the intestine is the most important system of the body, connected, among other things, with circadian rhythms, with the processes of sleep and wakefulness. And if a person has an imbalance of this system, he begins the process of accelerated aging. Therefore, it is important not only what we eat, but also when we eat. If we want to prolong our life, we need to try to eat high-quality healthy foods at about the same time.
Some researchers believe that in the future, microbiota will be taken from a person as a child and placed, for example, in liquid nitrogen. With age, everyone will be able to take samples of their ideal community of bacteria and thus rejuvenate the body.
Zombie Cells
Today, about 200 different molecular compounds are known that have been proven to slow down aging – and every year their number is growing. One of the latest discoveries is fucoxanthin, a brown pigment from some types of algae, which is being investigated by Russian scientists from the laboratory of Alexey Moskalev. This substance increases the life expectancy of several types of laboratory animals, increases stress resistance and quality of life. Scientists from the National University of Singapore, led by Professor Jan Gruber, have collected the most promising geroprotectors and applied them in various combinations on animals. As a result – for the first time without any genetic intervention, exclusively with the help of drugs – the life of experimental animals increased by 200%! If we translate this proportion to a person, we get about 150 years of life.
Doctors have long pinned their greatest hopes on rapamycin, a substance found on Easter Island.
It was discovered by Brazilian researchers as a product of the activity of special bacteria. At first, it was used as a drug that does not allow the transplanted organs to be rejected. But then scientists noticed its ability to prolong life. It turned out that it slows down an ancient biological reaction that almost all higher forms of life have. Rapamycin, as it were, informs the body that there is nothing to eat and puts it on the path of maximum preservation of what has been achieved to the detriment of further development. In mice, it prolongs life by tens of percent, however, it has side effects, including immunodeficiency (they, however, can be avoided by resorting to periodic, rather than constant use of the drug).
At the conference, Matt Koeberlein from the University of Washington said: for the first time, it was possible to show that the effects of rapamycin are much broader than slowing down cell aging. So, it changes the composition of the microflora and suppresses the development of periodontal disease, which often develops with age and through inflammation contributes to the development of cardiovascular diseases.
However, it is not yet possible to conduct clinical trials of rapamycin as a cure for old age in humans. But Professor Keberlein launched a project to combat aging in dogs (Dog Aging Project), where today any owner can include his pet. According to the researcher, rapamycin can increase the life expectancy of dogs by 25%, or by 2.5 years, assuming that on average dogs live about ten years. Dogs of medium and large breeds aged seven to eight years participated in the first stage of clinical trials, where the safety of the substance is determined. Now the scientist is recruiting volunteers for clinical trials of the second stage, which can show the effectiveness of the drug. In general, according to scientists, it is pets that will become the first large mammals to receive therapy for aging.
As for people, they should rely more on a fundamentally new class of drugs that appeared quite recently. The main author of the work, James Kirkland from the Mayo Clinic (USA), told Ogonka about him.
– The discovery of so–called senescent, or aging cells can be considered one of the most important achievements of science in recent years, - says Professor Kirkland.– These are special cells that have ceased to perform their functions, but have not died (in the near-scientific literature they were called zombie cells.– "O"). They destroy surrounding tissues, cause inflammatory and autoimmune reactions.
Professor Kirkland's team is busy searching for substances that specifically kill these cells in order to slow down aging at the tissue level. Dozens of such compounds have already been identified: clinical studies of their effectiveness are waiting for us soon. But so far none of them has been tested in humans as a drug for old age.
– This is a completely new type of drug, so it is difficult to say how it will act on a person, – says Professor Kirkland.– It's too early to talk about it yet.
Silver Tsunami
Already today, scientists can extend the life of a mouse in 15 different ways. Which of these techniques can be transferred to a person? Reliably – none: it is forbidden to test any drugs for old age in humans. So far, scientists can only treat senile diseases with the help of these developments.
The problem is that aging has not been recognized by WHO as a disease. As a result, large investors are not ready to invest in the development of drugs that
they will not be able to find a place in the market. In addition, according to scientists, it is unclear how to clinically investigate such drugs: if a person takes them, then he should not have a disease. But how can you prove that it didn't happen thanks to the pill? On animals that live a couple of years, it is easy to check by estimating mortality. But it is virtually impossible to conduct such large-scale epigenetic studies with people. The result: all over the world, the study of aging is funded, in fact, on a residual basis. Business does not invest in research projects, and grant funds and the state still do not consider aging as a problem, despite the "silver tsunami" threatening the world – global aging and disability of the population – and the collapse of the pension system.
It is known that the famous gerontologist Nir Barzilai has not been able to find money for clinical trials of the drug metformin on aging people for several years. He is missing half of the amount – $30 million. Metformin is a drug for the treatment of diabetes, and it was discovered, by the way, in Russia. Almost the only one of the promising geroprotectors that has been used in medicine for 50 years and has not actually shown any special side effects. The scientist wants to prove that he also relieves the symptoms of old age, but they do not give him money for this. The problem is that the drug is too cheap and it is impossible to get a patent for it, that is, from the point of view of profit, it is an absolute failure.
This behavior of pharmaceutical giants forces activists from science and small businesses to conduct their mini-studies, recruiting volunteers to test drugs on themselves. One of these "biohackers", the famous businessman Mikhail Batin, who finances scientific research in the field of aging, calls for a change in the mentality of the business elite, convincing it to pay for such clinical trials as part of charity. In his blog , he writes: "You can go to the crooks in Monaco for rejuvenation until you die, or inject placenta hydrate for 8000 euros, but it doesn't give anything special. You can figure out what you need yourself only by comparing the data of hundreds and thousands of people. Pay for the research for everyone and you will get the medicine for yourself." Batin predicts that the shaft of clinical trials on humans will be at the end of the decade, and this will give a serious breakthrough.
To feel old age
Most likely, medicines for old age will go to the market in a different way. Scientists are actively looking for so–called biomarkers of aging in the human body - substances whose level is associated with aging processes. Then they look at how they are affected by a potential cure for old age, and if the indicators return to normal (that is, to a more "young" state), then the medicine works. A lot of scientists in the world are busy searching for such markers.
– I think the main task that we have to solve is connected with biomarkers and with determining the exact biological age of a person, – says Claudio Franceschi to Ogonka. – Victory over aging in general will be associated with a personalized approach. After all, we all age in different ways - at the level of the body, organs and even cells.
Interestingly, completely different methods of prolonging life often lead to similar consequences – they change the work of the same genes, signaling pathways. At the same time, many interventions lead to the fact that, from the point of view of the work of the genome, male individuals begin to resemble female ones. But in female individuals there is no reverse effect. Why this happens remains to be seen.
– To stop aging, it is necessary to collect a huge amount of information, – continues Professor Franceschi. – Where and how a person was born, what vaccines he used, what he was ill with and how he was treated during his life, all possible results of tests and studies, and then using artificial intelligence to determine how your body is likely to be getting old and what you can do to stop it.
Similar services, although very imperfect, already exist in the USA and in Europe, but in Russia they do not exist – there are not even services that provide objective data about the same biological age. In other words, abroad it is already possible to determine your exact epigenetic age – the extent to which your genome has undergone changes during your lifetime. You can find out your glycan age – this parameter shows how complex carbohydrates (glycans) behave in your body, which is directly related to the age of cells. You can also find out your age by telomeres – the end sections of chromosomes, which can be used to calculate the estimated life expectancy.
All that is possible with us is to collect information independently and analyze it using an online tool developed by Insilico young.ai . Artificial intelligence technology analyzes about 40 blood parameters, compares them with age, ethnicity, etc., and then determines the biological age and estimated life expectancy. The free beta version of the system is still running.
When should a person think about aging in principle? Scientists believe that aging begins already at the earliest stages of development, and after 12 years it increases rapidly, doubling every eight years. Therefore, the earlier you start prevention, the more effective the result.
In a sense, scientists admit, the action of well-known geroprotectors makes them related to diet, physical activity and daily routine, which also systematically affect the physiology and epigenetics of the body. Hence the conclusion: while targeted gene and cell therapy of aging has not been developed, our main tools in the fight against it are healthy food and lifestyle.
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