The main killer
How to slow down aging
Andrey Konstantinov, "Expert"
Old age and death are the eternal causes of human suffering. Scientists believe that aging can be slowed down if you understand its mechanisms. The "Expert" met with leading researchers of aging to find out how much modern science has advanced in understanding aging and in creating methods that can slow it down.
Aging is the main killer on the planet. One hundred thousand people die every day from age-related diseases. The most common chronic conditions, such as cancer, atherosclerosis, diabetes or dementia, are united by a common mechanism of occurrence associated with the aging process. Starting from the age of forty, the risk of these diseases, as well as the risk of death, doubles approximately every eight years.
But to live with a bouquet of such diseases is one torment. Meanwhile, the global population of people over the age of sixty is growing faster than any of the younger age groups. In developed countries, in twenty years they will make up about a third of the entire adult population. There is only one way out: to prolong a healthy period of life as much as possible and to intensify scientific research that will slow down aging or even turn it off completely, so that medical costs stop growing with age, and a person remains productive. So far we know too little about aging – but we already know something important and we already know how to do something.
"I can extend the life of a healthy mouse by 30-40 percent – with the help of calorie restriction and a substance called rapamycin," Brian Kennedy, one of the world's most famous aging researchers, told us. – The idea, however, is not exactly that, but to increase the duration of a healthy life, so that the mouse remains young. And it also turns out: the same methods give about the same increase in the period of youth, healthy and active life. That is, we can already slow down aging in mice by more than a third. Will this happen to a person? We haven't actually tried it. After all, people are not very prone to healthy lifestyle, and here you have to be malnourished and drink medicine for decades. Even if you manage to extend your life by ten percent, it will already be very cool! But we still don't know if calorie restriction or rapamycin can prolong people's lives."
What is aging?
Aging is defined as the development of endogenous pathologies in the late period of life, which increases with time – and by definition it is clear that there is little good in it. We used to consider aging the norm of life, not a pathology, simply because there is nothing we can do about it.
Biologists search for the meaning of any phenomenon by studying its role in evolution. But why did evolution need living beings to frolic and multiply, begin to deteriorate and break down? The answer is known: to accelerate variability by rapid generational change, that is, to accelerate evolution itself.
"Imagine that a smart hare and a stupid hare live in the world," explains Academician of the Russian Academy of Sciences Vladimir Skulachev, dean of the Faculty of Bioinformatics and Bioengineering of Moscow State University. "They will breed stupid and smart rabbits while they are young, because there is no animal that would catch up with them, they will run away from anyone. But gradually they age, sarcopenia begins, that is, the number of muscle cells decreases in the muscles, hares become flabby and run slower and slower. And now the stupid hare, who does not know fox habits, will be eaten and will stop breeding stupid hares. And the clever one will get away from the fox by cunning and continue to multiply."
People with evolution have been confused for a long time, not the smartest ones reproduce the most successfully. But our genetic program is still the same, and we continue to age – only without any evolutionary meaning, but simply by inertia.
Is aging programmed?
What exactly is the mechanism that ensures aging? Maybe it's a simple accumulation of errors? But up to a certain point, errors are successfully repaired, cells are updated. And the life expectancy of different species varies too widely: for some reason, everything breaks down in a mouse in a couple of years, and in a whale - in a couple of hundred years.
Some biologists, including Vladimir Skulachev, believe that our genes have a program of slow suicide of the body, which triggers aging. "We carry the seeds of death within us," as the evolutionist August Weisman, who put forward this hypothesis, said. Others believe that we grow old and die from the work of the same mechanisms that provided us with growth and development in our youth – it's just that evolution did not take care to turn them off in time. Still others believe that aging is simply the accumulation of breakdowns in a variety of body systems, which the mechanisms of homeostasis gradually cease to cope with.
– Aging is a progressive decrease in the viability of the body with age, – says Corresponding member of the Russian Academy of Sciences Alexey Moskalev, head of the Laboratory of Genetics of Life Expectancy and Aging at the Moscow Institute of Physics and Technology. – But it happens at different rates in different people, so scientists are trying to identify criteria that allow us to judge the degree of aging regardless of chronological age – for example, by the amount of DNA damage. If we list these criteria, it will seem that aging is a set of very different phenomena that occur at different levels of the organization of living matter – molecular, cellular, at the level of cellular interactions and at the level of functional systems, such as respiratory or circulatory.
With age, more and more cells lose their ability to divide, tissue regeneration is disrupted – this is called cellular aging. Cells must be constantly updated, because they wear out. Some cells switch to a suicide program. Evolution has provided that if the DNA of a cell is severely damaged, then a program of self-destruction of the cell is launched so that its descendants will not be reborn into cancer cells.
Communication between cells is also disrupted. Let's say that in order for a stem cell to share, it must receive an instruction – a protein molecule. This molecule means that it is necessary to share and give rise to a certain type of blood cells. And if a cell receives the wrong signals, it either starts dividing rapidly, or stops, or gives rise to the wrong type of cells. As a result, changes such as thrombosis, atherosclerosis, blood supply to the heart muscles, brain, strokes, heart attacks are already occurring at the level of the circulatory system…
All these multi–level processes are the consequences of a violation of internal balance in a living system, when self-regulation mechanisms break down, which normally compensate and repair malfunctions in the body, maintain homeostasis. 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 like 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.
Is aging a disease?
– Whether aging is considered a disease is a question of terminology, it can be answered in different ways, – explains Alexey Moskalev. – There is, for example, such a point of view, formulated by Mikhail Blagoslonny, that aging is a set of diseases of old age. I am inclined to another concept formulated by Claudio Franceschi, who says that aging and age-dependent diseases have common pathophysiological processes. And age–dependent diseases are an example of accelerated aging. If these diseases are removed, aging will be sluggish, slow – so, for centenarians, typical problems of senile age begin only at the age of ninety. It turns out that if we identify the pathophysiological mechanisms of aging, then by influencing them, we can simultaneously remove age-dependent diseases and slow down aging.
But for this we need the personalization of medicine – after all, each person has his own aging profile. I heard a beautiful phrase in one report: "We are born copies, and we die originals." With age, we acquire very individual traits: someone has a bias in insulin resistance, someone has a tendency to inflammation, someone has genetic instability leading to cancer. I would like to make something like a diagram when you take a series of tests, and as a result, different aging mechanisms become visible, for example, in the form of columns of different heights. It is necessary to correct your problem areas – to reduce vascular age for someone, and to lengthen telomeres for someone.
The medicine of the future is preventive medicine. If we identify the mechanisms of aging and learn how to influence them, then age-dependent diseases will also be defeated.
And in modern medicine, no one recognizes aging as a disease – it is not beneficial to anyone, except for a few anti-aging enthusiasts. If aging is included in the list of diseases, different manufacturers of dietary supplements and cosmetologists will have to prove the safety and effectiveness of their methods in the fight against aging, and while this is not a disease, nothing needs to be done. Yes, and doctors: they do not understand how to treat a cold, what should they do with aging? To begin with, we need to give them some tools in their hands: diagnostic tests and syringes with anti-aging drugs. And if they are not, it is easier to recognize the naturalness of aging, then nothing needs to be done with it.
But now there is a positive trend: the International Classification of Diseases (ICD), the official list of diseases, thanks to the efforts of enthusiasts, began to include "age-associated conditions", that is, if not aging itself, then conditions associated with it. A couple of years ago, sarcopenia, the loss of muscle fibers, got into the ICD. And until recently, doctors considered it a normal part of aging. Muscles become flabby, a person stops walking, falls, dies, so what? He's old.
Why do some animals live hundreds of times longer than others?
– 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, a full member of the US National Academy of Sciences, told us. – After all, the life expectancy of animals of different species varies – from a few days to several centuries. It is clear that it is genetically determined and changes in one direction or the other as it evolves. The life span of mammals is clearly related to the duration of the maturation of the organism, the duration of childhood and the body weight of the organism – the larger the organism, the longer it usually lives. 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 two hundred years.
Put a fly, a mouse, a dog and a human in the same house – so that they breathe the same air, eat the same food – so that all environmental factors would be the same. And no matter what you do, a fly will live for three months, a mouse for a maximum of three years, a dog for a maximum of fifteen years, and a person can live for a hundred years. This suggests that the basis of life expectancy is still a genetic component. But if we consider the difference in life expectancy within a species, for example among all dogs, then the main role is already played by the environmental factor, and genes give only about a quarter of the contribution.
Some organisms have found a way not to age because they can renew their constituents by constantly removing old cells and producing young cells. For example, hydra.
There are also mammals that have managed to slow down aging very much. For example, many bats. Or a naked digger – a rodent the size of a mouse, but living ten times longer than a mouse. He has an amazing immunity to cancer. There were studies that were simply amazing: a carcinogen was applied to the skin, a hundred percent of mice had cancer, and diggers had not a single case. If you put him in a cell for twenty minutes without oxygen, he survives. At the same time, he is the only mammal that does not control his body temperature. He lives in his burrows in Africa, and when it's hot, he just goes down deeper, when it's cold, he rises.
We are trying to study such pairs of species that are as close to each other evolutionarily as possible. For example, an ordinary mouse and a naked digger. More than thirty years ago, the first diggers were brought to the laboratory, they live there and die mainly in fights with other diggers, although sometimes from other, not always clear reasons. The oldest of them is now thirty-eight years old, so we don't know yet what the maximum life expectancy of the diggers is.
Among other things, Vadim Gladyshev is known for having deciphered and was the first to investigate the genomes of two celebrities among animals with an unusually long life span – the naked digger and Brandt's moth.
– Brandt's moth is one of the bats that is found in Russia, it has been living for more than forty years. That is, in fact, it is not known how long she lives, there was just a program of animal ringing, she was ringed, and forty years later she was caught. It is one of the smallest mammals, weighing about four to eight 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 several features in her genes. For example, she has two genes disabled – the growth hormone receptor and the 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 organisms become smaller and live longer. A mouse whose growth hormone receptor gene was blocked has become dwarfed, and lives twice as long. But she has many other adaptations, that is, we are not talking about one mechanism that prolongs life, but about a whole set. It turns out that evolution led them to a long life – they found a niche where it is profitable to live for a long time.
In our genome, too, hundreds of genetic variants are already known that slightly affect life expectancy, but not a single gene is known that would make a very strong contribution to it.
What is the secret of centenarians?
It is not so easy to meet real centenarians – only one out of four or five thousand people lives to be a hundred years old. But Claudio Franceschi, a professor at the University of Bologna, has studied thousands of centenarians and super-centenarians (those over a hundred and ten years old) from different regions of the world over twenty years of research.
"The most noticeable and surprising difference between centenarians is that they live thirty to forty years longer, and most of them have avoided diseases associated with aging," Franceschi told us. – Even if they get sick, it's much later – for twenty or thirty years. Of course, most of them are women. Their already aged children are also in very good shape for their seventies. If you had centenarians in your family, your chances of living to a hundred years increase dramatically.
But centenarians from different places differ from each other – they have different genetics and different living conditions. In northern 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.
The longer a person lives after eighty years, the greater the role of genes in this. Centenarians have, for example, special protective genes, that is, protectors that prevent the development of age-related diseases. It was also possible to find some physiological mechanisms that distinguish centenarians. For example, we took lymphocytes and immune cells from them and found that, unlike other people's lymphocytes, in the absence of nutrients, they began to eat other cells, became "cannibals" in order to survive.
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 increases with time, has now become very popular, maybe even the majority of researchers today support it.
It sounds paradoxical, but if the immune system is to blame for everything, which causes inflammation, it turns out that immunity should not be increased, but reduced. That is why substances such as aspirin or the immunosuppressant rapamycin, under certain conditions, have shown themselves to be promising "medicines for old age" – they suppress inflammation.
And it also turned out that centenarians have important differences in the microbiota – the bacteria that inhabit the intestines. The bacteria that inhabit our body have a hundred times more genes than we do, and some of these genes seem to play an important role in longevity. Now it has become possible to transplant microbiota from one person to another. This method can cure some inflammatory bowel diseases, and it is possible, on the contrary, to infect obesity, as has been shown in mice. We still need to study this issue, but it may be more effective to transplant the microbiota of young people to the elderly.
How to prolong youth?
And while we are waiting for effective medicines and therapies, it is worth taking care of ensuring your own healthy longevity – especially since there are methods whose effectiveness has been confirmed by science. The main ones are well known: sleep quality, diet, daily routine, physical activity, social relevance…
"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, for us a lot depends on the way of life," says Claudio Franceschi. – I conducted a large project to study the nutrition of centenarians and became convinced of 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 tends to lose water, which has a very bad effect on the work of the heart, and not only on it. So please drink water. Not vodka! However, a glass of wine a day is more useful – but not because of the fashionable resveratrol, which is contained in red wine and supposedly prolongs life. It's just that wine helps relieve stress and is generally a good thing if you don't drink it in liters. It is also very good if the Mediterranean diet is enriched with vitamin D and folic acid, especially in old age.
But how long will we have to wait for the creation of therapies that can significantly prolong a healthy period of life?
– I have been studying aging for a quarter of a century, and I have the impression that we have only scratched the surface, – says Professor Franceschi. – A lot of disparate facts have been accumulated, but there are not enough concepts uniting them. Besides, the ways of prolonging life for Russians do not necessarily have to be the same as for Italians: you have a different genetics and a different environment. There are many ways to live up to a hundred years, I will say more: every centenarian has found his own, somewhat unique way."
Other researchers of aging are somewhat more optimistic, for example, Alexey Moskalev:
– In recent years, there has been a noticeable progressive movement in the field of aging research. A few years ago, everyone was figuring out the role of a particular gene in aging and longevity, that is, these were fundamental works. And now there is more applied research – studying the rate of aging and the biological clock built into us, looking for biomarkers that allow us to determine the biological age of different body systems, exploring specific intervention methods. More and more clinicians began to appear – now it is about half of the participants in conferences on the study of aging. A large number of comparative studies have appeared that have greatly influenced the course of the gerontology movement: Vadim Gladyshev, Vera Gorbunova, Andrey Siluyanov, who are now working in the USA, studying the aging processes in long-lived mammals. Vadim showed that if you put all these long-lived mammals in one row, then many changes in the activity of their genes are very similar. But it is impossible to pick up such a pill "from everything" – these changes concern the brain, kidneys, liver, and so on, and the changes in different tissues are specific, they do not have one common cause. A lot of attention has been paid to epigenetics – the mechanisms that regulate the activity of certain genes. In centenarians, it was found that the immutability of gene activity underlies such a long life. So, it is necessary to learn how to maintain this activity as long as possible by acting on epigenetic mechanisms.
Three drugs that slow down aging
The world is developing effective drugs that increase human life expectancy. Among them there are several drugs that scientists recognize as the most promising
Rapamycin
Mikhail Blagosklonny, Professor at the Roswell Park Cancer Institute:
– Rapamycin is secreted by a bacterium that lives on Easter Island. It produces it to suppress the growth of fungi, as fungi produce penicillin against bacteria. But aging is, to put it primitively, a continuation of growth. Therefore, fungi stop multiplying and growing, but begin to live for a long time. The mechanism of action of rapamycin is very similar to the mechanism of a low-calorie diet. We are very lucky that it works not only on fungi, but also on mammals. But since it suppresses growth, it is suitable only for adults. So far, it is used in organ transplantation to suppress immunity, but a lot of work is underway in various laboratories on its modifications that will allow it to be used as a geroprotector without side effects.
Metformin
Nir Barzilai, Director of the Institute of Gerontology at the Albert Einstein College of Medicine:
– Metformin is a medicine for the treatment and prevention of diabetes mellitus. This is the only promising geroprotector that has been used in medicine for sixty years and has not shown any special side effects. By the way, it was opened in Russia. And it turned out that it is effective not only for diabetes, but significantly prolongs the life of laboratory animals, helps prevent cancer, cardiovascular diseases and even cognitive disorders. I take it all the time myself, but mostly because I have diabetes.
Hyaluronic Acid
Vera Gorbunova, Professor at the University of Rochester:
– Hyaluronic acid is produced by the body of a naked digger – it seems that thanks to its protective properties, he lives for so long. The hyaluronic acid molecule has short and long forms. The short form is used for cosmetic purposes – in botox – to smooth out wrinkles. But it causes inflammation. And the long one, which the digger has, on the contrary, is anti-inflammatory and, apparently, anti-cancer: it's like telling the cells responsible for inflammation that they don't need to share anymore. But its molecules do not pass through the cell membranes: they are too large. If we want to treat cancer and aging with its help, we need to come up with a way to deliver it or develop molecules that will interfere with the work of proteins that destroy hyaluronic acid in our body. That's what we're doing."
Promising areas of research related to life extension
Geroprotectors are drugs that slow down aging and increase life expectancy. So far, however, most of the geroprotectors that researchers pin their hopes on prolong the life of laboratory animals, and as for humans, there are no guarantees.
Gene therapy is the introduction of new genes to a person or the modification of existing ones. It is used to treat genetic diseases, but in the future it is the most effective method of combating aging. And in general, access to the management of your own genetic program is some kind of fantasy, it's hard to even imagine its consequences.
Regenerative medicine is the cultivation of new organs from the patient's stem cells, followed by their replacement of the parts of the body that have become unusable. In clinics, they have learned to do this successfully so far only with a few not very complex organs: trachea, esophagus, vessels, but experiments on animals inspire optimism. Experts dream that someday there will be no need for organ transplants: we will learn how to renew them with our own stem cells right inside the body.
Cyborgization is a way to radically prolong life, involving the replacement of parts or the whole body with cybernetic analogues. For most organs, we have already learned how to make such analogues, but there is no need to create exact copies of our organs and bodies. The most difficult thing is to replace the brain. Enthusiasts dream of "uploading" consciousness to an artificial medium, but no one knows exactly how to do it. Until we understand what consciousness is, it seems extremely problematic to "upload" it somewhere.
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