Tales of Uncle Timus

Living longer does not mean living better

The duration of human life is increasing: we live longer than our ancestors, and our children, apparently, will live longer than we. According to the World Health Organization, in 2000, the share of people over 60 years old was about 10% of the universal population and, according to forecasts, will be 22% by 2050 [1] . This trend is inherent in more developed and developing countries thanks to modern medicine and reasonable health policy.

At the same time, “living longer” still does not mean “living better”: older people often get sick, are forced to constantly take medicines. So, among people over 65 years old, mortality from influenza above 80% [2] . Vaccinations are ineffective, the risk of developing autoimmune diseases is increasing. Older people often suffer from autoimmune diseases. All this suggests that over the years, some mistakes accumulate in the immune system. And if these mistakes could be fixed, then the quality of life of the elderly would improve.

Over the past years, a large number of theoretical data on molecular and cellular mechanisms of aging immunity have been collected. There are a lot of information on this issue, and now the question "Is it possible to rejuvenate immunity?" Scientists give an encouraging answer.

Congenital and acquired immunity

The basis of the immunity are three events - the penetration of infection inside the body, then recognition of the “enemy” and, finally, the destruction of it (or at least neutralization). Immunity is traditionally divided into congenital and acquired. Congenital immunity we have regardless of whether we have encountered an infection earlier or not. Studies of aging of such immunity are currently underway, but the results are still contradictory.

Acquired , or adaptive , immunity is the ability to protect itself from foreign microorganisms or toxins, provided that the body has already encountered these objects. That is, in addition to the recognition and destruction of the “stranger”, memory mechanisms are included. This means that cells that have already encountered infection should somehow remain and, in the event of a repeated infection, recognize it and destroy it faster and more efficiently.

The principle of operation of the vaccine is also based on the property of memory - weakened or dead microorganisms, or only molecular “badges”, which are this or that type of microorganism on the surface, are introduced into the body. It is according to these special “badges”, or, expressed in the scientific language, antigens, the cells of the immune system recognize, “their own” or “alien”. As we have already mentioned, autoimmune diseases are often found in older people, and susceptibility to infections is increased, and vaccines are ineffective. Further, we learn that these at first glance unrelated problems have much in common.

The role of T-lymphocytes in the immune response

We will not consider the mechanisms of the work of all immunity cells in detail - weighty books are written on this subject, every year there is more and more information. The immune response is always a performance with a large number of actors. Consider the most common scenario. The infection enters the body - it can be a virus that enters a healthy cell, or microorganism. C cells of congenital immunity react first - they capture cells affected by the virus, or microorganism itself and expose an antigen on their surface.

Then other immunity cells, called naive T-lymphocytes (“naive” means “encountering antigen for the first time”), are obtained using the antigen-set signal to action.

On the surface of T-lymphocytes there are special receptors that can recognize antigens. These receptors are called: T-cell receptors (TCR). The biologically mechanism of T-cell recognition is the binding of a suitable TCR and antigen. Imagine that several knuckle keys are not too reliable-the antigen of the T-cell receptor occurs in about the same way. TCR can bind several antigens, and, conversely, the antigen can be tied to several TCR.

After the naive T-lymphocyte met with the infection, it becomes activated: it begins to actively share. Moreover, part of its clones turns into the so -called effector cells, the rest into memory cells. Effector cells either produce special molecules that activate other immunity cells (T-Halper), or kill affected cells (T-killers). Memory cells are preserved and in case of re -meeting with the same infection provide a more effective immune response.

Degradation of Timus

T-lymphocytes are born in Timus-a special organ of the immune system. It is located in the upper chest.

Timus degrades with age. This process, called Involution , begins during puberty, and by old age the timus fabric is almost completely replaced by adipose tissue. Along with the degradation of the thymus, the production of T-lymphocytes is almost completely stopped. According to the latest data, the release of T-lymphocytes from Timus, albeit very small, remains even in people who have reached 100 years of age [3] .

How do long -livers differ from ordinary mortals?

Over the years, Timus produces less and less cells, but various infections attack a person throughout his life. Therefore, the supply of naive T cells that can fight new infections is gradually exhausted.

In addition, in the body there are constant random meetings of naive T cells and viruses that are constantly present in the human body.

One of these viruses is cytomegalovirus (CMV). Infection with this virus often occurs imperceptibly or expressed as ordinary SARS. Moreover, more than 90% of people around the world are its carriers and have antibodies in the blood to him. After the meeting of naive T-lymphocytes and CMV, T-lymphocyte is activated and the growth of the clone population specific to this virus. Gradually, the physiological niches are filled with such clones, and since the number of immune cells in the body is regulated by feedback, there is a decrease in the production of new immune cells. That is, the body receives a signal that there are a lot of immune cells and you can no longer produce them. Moreover, almost all of these cells are useless.

It is remarkable that people who overcome the threshold of 70 years have more naive T cells and diverse set of T-cell receptors compared to people who have not yet turned 70 years old. Also, long-livers are less pronounced among the populations of cells-clones-that is, cells that occurred from one activated T-lymphocyte. Perhaps it is these features of immunity that allow long -lived to cope with infections and be healthier. On the other hand, “selection” is also possible - people with reduced immunity, unfortunately, less often become long -lived [4] .

Autoimmune diseases

At the beginning of the article, it was stated that autoimmune diseases accumulated with age may have general causes. And these reasons have already been mentioned several times - the involution of Timus and the growth of cell populations that occurred from one once activated cell. It is worth a reservation once again: immunity is a very complex system, and we consider the most common case, using as few special words as possible. Thus, our story has only five actors: Timus, T-lymphocytes (T-killer, T-Halper), T-cell receptors (TCR) and antigens. But here we will get acquainted with another type of cell-regulatory T-cells.

All cells in the body carry an identification sign, and, unfortunately, some T-lymphocytes can perceive them as an antigen. Some organs are isolated from general blood flow and never encounter T-lymphocytes, such as thyroid gland. But if the injury occurred and the immune cells of the blood collided with the thyroid cells, the former will develop an immune response against the latter.

This will happen because the thyroid cells wear tags that the cells of the immune system have not yet been seen and perceived as “strangers”, that is, as antigens. The remaining organs are not protected by such a capsule, and normally Timus kills T-lymphocytes, the TCR of which can perceive marks on the host cells as antigens. But still a small amount of T-lymphocytes hostile to the body, Timus misses-and they wander somewhere on the periphery. Their action is restrained by suppression mechanisms (suppressions)-special T-regulatory cells. They are also born in Timus. With age, Timus produces less and less regulatory cells, and random T cells directed against the owner’s body, activating, develop a full-fledged answer. As is already known, activated T-lymphocyte is actively shared and, thus, the population of cells aimed at destroying the owner’s tissue becomes impressive after some time.

Methods of rejuvenation of immunity

So, we got to the answer to the question at the beginning of the article: is it possible to rejuvenate immunity and how to do this. We saw that the main reason for the aging of immunity, with all the ensuing consequences, is the age -related involution of Timus.

Since the late 80s of the last century, it is known that the involution of Timus has been directly related to sex hormones that begin to actively be developed in the puberty period. Multiple studies [5, 6] showed that in mice, castrated before puberty, the work of thymus improves. Moreover, the number of T-lymphocytes predecessors, which has decreased over the years, normalizes after castration [7] . The fact is that all subpopulations of thymocytes (immature T-lymphocytes), as well as the stromal cells of the thymus (that is, cells that create for thymocytes the necessary environment for development) have receptors for sex hormones in both women and men.

The elimination of sex hormones can be carried out not only surgically, but also by prescribing drugs, such as analogues of Gonadoliberin - a hormone that stimulates the activity of the testes.

Another version of the timus rejuvenation is the use of signal molecules necessary for creating thymocytes in the thymus: cytokines and growth factors. Moreover, it is possible to somehow influence the biological mechanisms by which the range of cytokines in the thymus is regulated (that is, do not introduce signal molecules themselves, but somehow force the cells to produce the necessary ones).

In 2013, clinical tests of KGF (growth factor of keratinocytes) on the functions of thymus in adults (18-50 years) were carried out, the results were quite encouraging (NCT01712945). Another interesting fact (and we mentioned it at the beginning of the article) is that with age, the timus timus is replaced by fat cells. At the same time, Timus is quite well restored with a low -calorie diet. Most likely, the “hormone hunger” - Grelin (ghrelin) [8] contributes to this. Thus, therapy can be of two types: a low -calorie diet or the use of Grelin.

Conclusion

So, the age-related weakening of the immune system, which causes low resistance to infections (and immunity to vaccines) and autoimmune diseases, occurs primarily due to the aging of thymus. Timus begins to degrade in the first year of life, but this process becomes noticeable during puberty, as a response to the increased production of sex hormones - and this fact makes us think.

Perhaps in this phenomenon a deep philosophical meaning is laid: we must grow old and die in order to give life to the next generation. And this, of course, is fine. But, on the other hand, the aging of Timus can be turned, and the easiest way is to reduce the amount of food consumed.

I would like to get a little distracted from biology and think about the connection of “sexuality - food”: these concepts have long been related in art, and in particular, in literature. For example, Pushkin’s famous champagne in Evgenia Onegin says this way:

AI lover is similar
Shiny, windy, alive
And wayward and empty ...

And here, biology again throws us food for thought: it turns out, as shown in experiments on mice, Grelin, “hormone hunger”, which has a positive effect on immunity, weakens sexual behavior [9, 10] .

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