Methods of immune rejuvenation
Tales of Uncle TimusDaria Morgacheva, "Trinity Variant" No. 18-2014
Living longer doesn't mean living betterThe duration of human life is increasing:
we live longer than our ancestors, and our children will probably live longer than we do.
According to the World Health Organization, in 2000, the proportion of people over 60 years of age was about 10% of the human population and, according to forecasts, by 2050 it will be 22% [1] (see here and further links in the original article – VM).
This trend is more common in developed and developing countries thanks to modern medicine and reasonable health policy.
At the same time, "living longer" still does not mean "living better": elderly people often get sick, have to constantly take medications. Thus, among people over 65 years of age, the mortality rate from influenza is above 80% [2]. Vaccinations are ineffective, the risk of developing autoimmune diseases increases. Elderly people often suffer from autoimmune diseases. All this suggests that over the years, some errors accumulate in the immune system. And if these mistakes could be corrected, the quality of life of the elderly would improve.
Over the past years, a large amount of theoretical data has been collected on the molecular and cellular mechanisms of aging immunity. There is a lot of information on this issue, and now scientists give an encouraging answer to the question "Is it possible to rejuvenate the immune system?".
Innate and acquired immunityImmunity is based on three events – the penetration of infection into the body, then the recognition of the "enemy" and, finally, its destruction (or at least neutralization).
Immunity is traditionally divided into innate and acquired. We have innate immunity regardless of whether we have previously encountered an infection or not. Studies on the aging of such immunity are currently underway, but the results are still contradictory.
Acquired, or adaptive, immunity is the ability to protect yourself from foreign microorganisms or toxins, provided that the body has already encountered these objects. That is, in addition to recognizing and destroying the "alien", memory mechanisms are activated. This means that cells that have already encountered an infection must somehow survive and, in case of repeated infection, recognize it and destroy it faster and more efficiently.
The principle of operation of the vaccine is based on the property of memory – weakened or dead microorganisms are introduced into the body, or only molecular "badges" that are worn by one or another type of microorganism on the surface. It is by these special "badges", or, in scientific terms, antigens, that the cells of the immune system recognize whether it is "their own" or "someone else's". As we have already mentioned, the elderly often have autoimmune diseases, increased susceptibility to infections, and vaccines are ineffective. Next, we learn that these seemingly unrelated problems have a lot in common.
The role of T-lymphocytes in the immune responseWe will not consider in detail the mechanisms of work of all immune cells – weighty books have been written on this topic, every year there is more and more information.
The immune response is always a performance with a large number of actors. Let's consider the most general scenario. The infection enters the body – it can be a virus that gets inside a healthy cell, or a microorganism. The cells of innate immunity react first – they capture the cells affected by the virus, or the microorganism itself and expose the antigen on their surface.
Then other immune cells, called naive T-lymphocytes ("naive" means "encountering the antigen for the first time"), receive a signal to action with the help of the exposed antigen.
On the surface of T-lymphocytes there are special receptors capable of recognizing antigens. These receptors are called T-cell receptors (TCR). Biologically, the mechanism of recognition by T cells is the binding of a suitable TCR and an antigen. Imagine that several master keys fit to a not too reliable lock - about the same way the antigen is captured by the T–cell receptor. A TCR can bind multiple antigens, and conversely, an antigen can be bound by multiple TCR.
After the naive T-lymphocyte has encountered an infection, it becomes activated: it begins to actively divide. At the same time, some of its clones turn into so–called effector cells, the rest into memory cells. Effector cells either produce special molecules that activate other immune cells (T-helpers), or kill affected cells (T-killers). Memory cells are preserved and, in case of a repeat encounter with the same infection, provide a more effective immune response.
Degradation of the thymusT-lymphocytes are born in the thymus, a special organ of the immune system.
It is located in the upper part of the chest.
With age, the thymus degrades. This process, called involution, begins during puberty, and by old age the thymus tissue is almost completely replaced by adipose tissue. Together with the degradation of the thymus, the production of T-lymphocytes decreases significantly and almost completely stops. According to recent data, the output of T-lymphocytes from the thymus, albeit very small, persists even in people who have reached 100 years [3].
The thymus of a newborn. A drawing from Grey's Anatomy (1918 edition).
Over the years, the thymus significantly decreases in size
How do centenarians differ from ordinary mortals?Over the years, the thymus produces fewer and fewer cells, but a variety of infections attack a person throughout his life.
Therefore, the stock of naive T-cells capable of fighting new infections is gradually being exhausted.
In addition, there are constant random encounters 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 unnoticed or is expressed as a common SARS. At the same time, more than 90% of people around the world are carriers of it and have antibodies to it in their blood. After the meeting of the naive T-lymphocyte and CMV, the activation of the T-lymphocyte occurs and the population of clones specific to this virus increases. Gradually, 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 quite a lot of immune cells and they can no longer be produced. At the same time, almost all of these cells turn out to be useless.
It is remarkable that people who have crossed the threshold of 70 years have more naive T-cells and a more diverse set of T-cell receptors compared to people who have not yet turned 70 years old. Also, populations of clone cells are less pronounced in centenarians - that is, cells descended from a single activated T-lymphocyte. Perhaps it is these features of immunity that allow centenarians to cope better with infections and be healthier. On the other hand, "selection" is also possible – people with reduced immunity, unfortunately, are less likely to become centenarians [4].
Autoimmune diseasesAt the beginning of the article, it was stated that autoimmune diseases accumulated with age and weakened immunity may have common causes.
And these reasons have already been mentioned several times – thymus involution and the proliferation of cell populations that originated from one once activated cell. It is worth mentioning once again: immunity is a very complex system, and we consider the most general case using as few special words as possible. Thus, our story has only five actors: thymus, T-lymphocytes (T-killer, T-helper), T-cell receptors (TCR) and antigens. But here we will get acquainted with another type of cells – regulatory T cells.
All cells in the body carry an identification mark, and, unfortunately, some T-lymphocytes can perceive them as an antigen. Some organs are isolated from the general blood flow and never encounter T-lymphocytes, for example, the thyroid gland. But if an injury has occurred and immune blood cells collide with thyroid cells, the former will develop an immune response against the latter.
This will happen because the cells of the thyroid gland carry such labels that the cells of the immune system have not yet seen and are perceived as "strangers", that is, as antigens. The rest of the organs are not protected by such a capsule, and normally the thymus kills T-lymphocytes, whose TCR can perceive tags on host cells as antigens. But still a small number of T-lymphocytes, hostile to the body, the thymus misses – and they wander somewhere on the periphery. Their action is restrained by suppression mechanisms – special T-regulatory cells. They are also born in the thymus. With age, the thymus produces fewer and fewer regulatory cells, and random T cells directed against the host organism, activating, produce a full-fledged response. As is already known, the activated T-lymphocyte actively divides and, thus, the population of cells aimed at destroying the host tissue becomes impressive after some time.
Methods of immune rejuvenationSo, we have come to the answer to the question posed at the beginning of the article: is it possible to rejuvenate the immune system and how it can be done.
We have seen that the main cause of aging of the immune system, with all the ensuing consequences, is age-related thymus involution.
Since the late 80s of the last century, it has been known that thymus involution is directly related to sex hormones that begin to be actively produced during puberty. Multiple studies [5, 6] have shown that thymus function improves in mice neutered before puberty. Moreover, the number of T-lymphocyte progenitor cells, which has decreased over the years, normalizes after castration [7]. The fact is that all subpopulations of thymocytes (immature T-lymphocytes), as well as stromal cells of the thymus (that is, cells that create the environment necessary for thymocytes to develop) have receptors for sex hormones in both women and men.
Elimination of sex hormones can be performed not only surgically, but also by prescribing drugs, for example, analogues of gonadoliberin – a hormone that stimulates the activity of the testes.
Another option for rejuvenation of the thymus is the use of signaling molecules necessary for the creation of thymocytes in the thymus: cytokines and growth factors. Moreover, it is possible to somehow influence the biological mechanisms by which the spectrum of cytokines in the thymus is regulated (that is, not to introduce the signaling molecules themselves, but somehow force the cells to produce the necessary ones).
In 2013, clinical trials of the effect of KGF (keratinocyte growth factor) on thymus function in adults (18-50 years old) were conducted, the results were quite encouraging (NCT01712945). Another interesting fact (and we mentioned it at the beginning of the article) is that with age, thymus tissue is replaced by fat cells. At the same time, the thymus recovers quite well with a low-calorie diet. Most likely, the "hunger hormone" ghrelin (ghrelin) contributes to this [8]. Thus, therapy can be of two types: a low-calorie diet or the use of the drug ghrelin.
Methods of immune rejuvenationSo, age-related weakening of the immune system, which is the cause of low resistance to infections (and immunity to vaccines) and autoimmune diseases, occurs primarily due to aging of the thymus.
The thymus begins to degrade in the first year of life, but this process becomes noticeable during puberty, as a response to increased production of sex hormones – and this fact makes you think.
Perhaps there is a deep philosophical meaning in this phenomenon: we must grow old and die in order to give life to the next generation. And that's certainly fine. But, on the other hand, thymus aging can be reversed, and the easiest way is to reduce the amount of food consumed.
I would like to digress a little from biology and think about the connection "sexuality – food": these concepts have long been linked in art, and in particular, in literature. For example, Pushkin says about the famous champagne in "Eugene Onegin" as follows:
Ai is like a mistress
Shiny, windy, lively
And wayward and empty…
And here biology again gives us food for thought: it turns out, as it was shown in experiments on mice, ghrelin, the "hunger hormone", which has a positive effect on immunity, weakens sexual behavior [9, 10].
Portal "Eternal youth" http://vechnayamolodost.ru10.09.2014