Eternal life without diseases
When will a person be able to overcome diseases and live forever?
Prepared by Nadezhda Plotnikova, "Real Time"
It is undesirable to block the aging process, it is very important, explains Kristina Kitaeva, lecturer at the Department of Genetics at the Institute of Fundamental Medicine and Biology of KFU. At the same time, there are already therapeutic strategies that will eventually lead to the creation of real "elixirs of youth". "Real Time" provides a transcript of her lecture within the framework of the project "Pro-Science in KFU" called "The Night after A.D." about when a person will be able to overcome diseases and live forever.
How people used to die
No matter how sad it is to realize this, but every living person on earth will die someday. Yes, aging and death are integral parts of human existence as a biological species. However, man managed to win a wonderful tool in the evolutionary lottery – intelligence, which, I am sure, will allow him to change the existing order of things.
Previously, the issues of gaining eternal youth and immortality were most often somewhere in the field of philosophy and religion, but in the process of accumulating knowledge about how a living organism works, gerontologists took up the task.
Gerontology is a field of knowledge that studies the mechanisms of aging of organisms, and at this stage of the existence of biological science, perhaps, gerontology is one of its most funded areas. Large corporations and just very rich people of the world invest huge amounts of money in research aimed at finding those very pills for old age and "elixirs of youth".
If we are so actively talking about death and focusing attention on it, then I suggest we turn to the past, see why people died before.
Firstly, it should be said that earlier people lived much less, died much earlier, infant mortality was very high.
And the reason for all this was infections – measles, smallpox, tuberculosis, syphilis, bubonic plague. These diseases claimed millions of lives, and everyone who became ill with this infection was actually doomed to death. But everything has changed.
Everything changed after the invention of antibiotics and vaccines. It was antibiotics and vaccines that stopped the terrible epidemics that claimed millions of lives in the world. Widespread vaccination allowed us to send into the past, for example, the smallpox virus, which remained only as museum samples in two laboratories of two countries of the world – Russia and the USA. And I am sure that this time, when the planet is in danger again, the vaccine will save humanity again.
What is aging?
But fast forward to the present. So, people stopped dying so massively from infections. The standard of living and hygiene has increased, and along with all this, life expectancy has increased. Humanity has finally learned the beauty of aging and the diseases that are associated with aging.
These diseases include heart and circulatory diseases, malignant neoplasms, respiratory diseases and neurodegenerative diseases. These types of diseases are associated with aging, and scientists have asked the question: what if aging is suspended and reversed, and is it possible at all?
Before trying to answer this difficult question, let's first look at what aging is, what does it represent? Is it the wear and tear of the system that inevitably occurs with age, or maybe it's a genetic program that triggers the aging process from the moment of conception? The question remains open, although researchers have recently been leaning towards the second option.
What characterizes aging? First of all, it is an increase in the probability of death with age. The older we get, the more likely we are to die. In addition, it is a deterioration or loss of the functionality of cells, tissues, organs and, above all, it concerns the reproductive system.
Also, one of the characteristics of aging is the accumulation of damage in genes, which are reflected, in turn, in cells, in organs and in the general form of this sad picture of old age.
However, there is a theory that says that aging actually provided an evolutionary advantage to species. Longevity is actually not a very good strategy, because longevity forces, for example, ancestors and their offspring to compete with each other for resources. In addition, if an organism lives for a very long time, then it does not have a special need to multiply. And if there is no aging, then there is no need to create offspring. While the organism reproduces, it is noticeable for natural selection. It is the change of generations that allows the species to survive. It is the death of less adapted, older individuals and the birth of new, more adapted to the changed environmental conditions of new individuals that allows the species to survive.
In the 50s, this theory was somewhat advanced a little deeper, closer to genes, and it was suggested that perhaps alleles or combinations of genes that at some age have a destructive effect on the body, for example, cause hormone-dependent cancer, remain in the population only because at a younger age, when reproductive the flowering of the organism, these genes provide an advantage to the body. Thus, they improve its fitness, that is, what works well in an earlier period has a destructive effect on the body later. Such are the opposite functions of one gene, but we will return to this a little later.
So, when does aging begin? Maybe from the moment of conception or from birth, perhaps from the period of the lowest mortality, well, from about 9 years old?
Yes, indeed, a person has a period of the lowest mortality, it is derived simply statistically: before the age of 9, a person has a much higher probability of dying and after 9 years, the probability of death also creeps up. Or maybe aging begins with puberty, when the body enters the path of puberty? Or when the organism is already formed as a sexually mature individual, will this aging begin? Or does aging begin when the obvious first signs appear, that is, after about 40? The question remains open.
Theories of aging: Hayflick limit, free radicals, Horvath clock
The most popular of them is the telomeric theory, which states that during the life of a cell, telomeres are formed on its chromosomes at the end sections – protective caps of nucleotides. They stabilize and protect the chromosome from destruction during cell division and are constantly shortened. They are shortened until they reach a minimum. And when the size of telomeres reaches a minimum, the cell stops dividing, it reaches the point of no return, it experiences replicative aging. This phenomenon is named after the scientist Hayflick. That's what the Hayflick limit is called, when the cell has reached the point of no return and will never share again.
However, the accumulation of such cells in tissues and organs eventually leads to the fact that the regenerative potential and homeostasis of tissues is greatly reduced, and as a result we see numerous bad effects from this process. So, there are cells in which a special enzyme works – telomerase, which builds up these sections of telomeres lost as a result of division.
The most obvious kind of cells in which telomerase works are stem cells. Stem cells are a pool of cells that allow organs and tissues to regenerate, and these cells simply need to have this enzyme in working order. But what happens? Maybe if we start telomerase in other cells of the body, we will be able to provide them with immortality? And yes and no, most likely, it's not that simple.
Unfortunately, experiments conducted on obsolete cells, which included the enzyme telomerase anew, led to the fact that the cell began to divide uncontrollably. At the same time, her functions were already lost, she turned out to be immortal, and what did we get at the output? Yes, cancer cells. And at the moment, unfortunately. there is no way to bypass this malignant cell degeneration by launching telomerase yet.
The second theory of aging is the theory of free radicals. What is its essence? Reactions are constantly occurring in the body. The enzymes interact with the substrate, and a free radical is obtained as a by-product of this reaction. Basically, these are reactive oxygen species, and the more such reactions occur in the body, the more free radicals are released. These free radicals are molecules that lack one electron on the external electron cloud, and because of this, their properties, the free radical is ready to react with anything, just to regain the lost electron. In the process of these reactions, it changes, breaks down the cellular structures with which it meets. That is, the more the reaction occurs in the cell, the more free radicals and the more damage accumulates in the cell. Theoretically.
This theory was confirmed indirectly in experiments on mice that were calorie-restricted. Scientists divided the mice into groups. One group was given a minimum of calories, others ate well. And mice that ate less and moved less lived longer than their more well-fed and energetic counterparts. In addition, insulin and insulin–like growth factors may also be involved in this process, because everything is interconnected - nutrition and insulin, the sensitivity of cells to insulin.
The experiment, or rather, clinical observations of diabetic patients who took metformin, showed that these people somehow lived longer than those who did not have diabetes and, accordingly, did not take the drug.
And finally, the third theory of aging. This is the newest theory, the youngest, it is called the theory of the epigenetic clock or "Horvath clock". This theory is based on the methylation process. Methylation is the process of attaching a methyl group to a cytosine at certain DNA sites (these are called spg sites). When this methyl label is attached to the spg site, the gene actually turns off, because transcription factors can no longer interact with the DNA site and begin the transcription process. So, it was found out that this epigenetic landscape, these marks are numerous, placed on the human genome, they are constantly changing in the course of life. Some genes turn on, others turn off from the embryo to old age, the epigenetic landscape changes the body.
In general, this theory is quite young and very, very promising, and it explains quite well the essence of the processes that occur in cells. And if we learn to understand and act on the process of setting these marks in the body over time, then perhaps we will get the key to that very immortality and getting rid of all diseases that are associated with aging.
In addition, the theory of the epigenetic clock, the "Horvath clock", was even involved in a small forensic plot. I think you know that the situation with migrants and refugees is very difficult in Europe and, according to European laws, European countries cannot refuse asylum to persons who have not reached the age of majority. So, in one of the German cities, one of the law enforcement officers attempted to find out the real age of one of the minor refugees with the help of just the "Horvat's watch". Blood samples were collected from this person and sent to a California laboratory, where they were tested. As a result, it turned out that the person who presented himself as a minor is a person who is well over 20, rather closer to 30. It is not known for sure how this story ended, but the technology is very, very promising.
In addition, the epigenetic clock can be reset to zero. With the help of, for example, Yamanaki factors or the "Yamanaki cocktail". This cocktail is a combination of factors that turn a highly specialized differentiated adult cell into a pluripotent cell, essentially a stem cell, which can already give rise to absolutely any cell in the body. And of course, the phenomenon of zeroing cells using the "Yamanaki cocktail" was discovered much later. Yamanaki received the Nobel Prize in 2006 for this combination of factors that return the cell to the stem state, and then, of course, there was no talk about the "Horvath clock". The information that this really happens in cells was obtained much later, but the fact itself is extremely interesting, because induced pluripotent stem cells are now being actively studied in the field of regenerative medicine in the context of growing organs and tissues in a laboratory.
What are aging cells like
Firstly, I must say that aging cells are very important. In the 2020 article, the author mentioned two types of aging cells – these are D-aging cells and H-aging cells.
Both of them perform a number of very important functions in the tissues during their aging, in particular, they contribute to embryogenesis, normal homeostasis during pregnancy, the development of an immune response, suppression of oncogenesis, wound healing, and they also contribute to the passage of the fetus through the birth canal.
However, if an aging cell (when it reaches its proper aging) is in the tissue, this cell must be removed from the tissue very quickly. If this is not done, then the cell can slightly change the principle of action in tissues, for example, a D-aging cell is able to accept the so-called SASP phenotype, that is, it is a phenotype associated with aging. What is it characterized by? The cell begins to emit an abnormal amount of inflammatory factors that cause the destruction of neighboring tissues, cause local inflammation. They cause dysfunction of stem cells, which, let me remind you, are a regenerative pool, and can also contribute to the malignant degeneration of neighboring cells, and the aged D-cells themselves with a dangerous SASP phenotype can become cancer cells. And that is why targeting the cleaning of such cells, already aged, is very important, it is one of the very promising therapeutic strategies. Unlike, for example, those strategies that are aimed at blocking the aging process itself. It is undesirable to block the aging process, it is very important.
Elixirs of youth
The aging process actually plays a number of important functions. Yes, when we are young, the aging process plays for us. When the body becomes older, the aging process of cells plays against us.
Such a dual behavior of the same process in different periods of life is called antagonistic pleiotropy, that is, we can't just get rid of aging. The aging process plays a crucial role in the development of the body, but at the same time we must somehow contribute to the removal of already aged cells.
The topic is very interesting, and I hope that therapeutic strategies will be found very soon, for example, with the help of special drugs – the so-called potential "elixirs of youth" or senolytics.
Yes, researchers have discovered these compounds or discovered previously unknown properties of drugs. For example, the drug "Dasatinib", which is one of the elements of chemotherapy, or "Rapamycin", which is actually a very powerful immunosuppressor used for patients to whom donor organs have been transplanted, so that the patient's immune system does not attack these transplanted organs, and rejection does not occur.
So, these drugs ("Quercetin", "Fizetin", "Luteolin", cardiac glycosides, "Curcumin", "Navitoclax", "Tanespimycin", "Geldanamycin" and others) may have the same rejuvenating effect, although researchers who study these new properties of known drugs or recently created especially as senolitics, they are very careful in their formulations and conclusions. These drugs have a huge number of side effects and the expediency of their use in the context of rejuvenation is still unclear.
Well, a person also has a lot to strive for, because together with us on earth there are unique species of animals that somehow escaped the fate of aging. Yes, they age, but not at all like people. They do not lose their reproductive functions, their probability of death does not increase with age, that is, these animals have somehow changed the aging process in their body. They were called animals with negligible aging, and today they are very interesting objects to study.
Here, for example, is a naked digger, a favorite object of research for gerontologists all over the world. This is such a small rodent, a mammal that lives an order of magnitude longer than its fellows in the squad. Or the Greenland shark, which has "blown up" the Internet for the last, probably, two years, because researchers have discovered an individual that, for a moment, is more than five hundred years old. These fantastic animals make researchers look forward to the future of man with hope.
Well, besides, do not forget about those approaches that are already being used in medicine, at least the first attempts are being made. For example, genome editing. Now there are already approved drugs based on viral vectors that are embedded in the human genome, and reduce the causes of the disease to zero. Or, for example, the successes of regenerative personalized medicine.
By the way, our laboratory also conducts research in this area, and the results of my colleagues' work are simply inspiring. In addition, there is biohacking. Biohacking, in principle, combines all of the above together.
Therefore, I am sure that humanity is not just standing in front of the door to a wonderful future, where each person will have his own master key from a gene-cell drug. We have already opened this door and are already taking a step into this future today.
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