04 December 2015

Aging of cells and aging of the body

Why do cells age

Yulia Kondratenko, "Biomolecule" 

Cell aging, unlike the aging of the body, is an important and necessary process. This article describes how the good intention of the cellular community to live harmoniously as part of the body eventually leads to such a harmful phenomenon as the aging of living beings. And also about how to deal with this harmful phenomenon.

The aging of cells is not the same as the aging of the body. In the great and mighty English language, different words are even used to denote these concepts: aging – for the aging of the body, and senescence – for cellular aging. It's much easier to avoid confusion this way. Senescence is a mechanism that weeds out unreliable cells that are highly likely to become cancerous. In naked diggers, famous for the almost complete absence of aging at the body level (aging), as well as resistance to cancer, the cellular aging system (senescence) works very actively and efficiently, ruthlessly screening out all cells in which something even a little suspicious is happening [1]. The manifestation of aging at the body level is not a direct consequence of aging of damaged cells. An old organism does not consist of cells with signs of cellular aging, it only has a higher proportion of them. For example, in young mice, the proportion of cells with signs of senescence is 8%, and in very old individuals this proportion increases to about 17% [2]. In some organs – for example, the heart, skeletal muscles and kidneys – the proportion of cells with signs of cellular aging does not grow at all during life, although these organs themselves undoubtedly work worse with age. Consequently, the aging of an organism is more complicated than the sum of the aging of its individual cells (Fig. 1), and it occurs not least due to subtle violations of the regulation of intercellular interactions. Unfortunately, without understanding the intricate cellular relationships and the complex changes they cause in individual cells, aging cannot be understood.


Figure 1. Nine key signs of aging of the body (according to the authors of the article [40]). These signs are inextricably linked: for example, the shortening of telomeres in a complex way 
it leads to deterioration of mitochondrial function [41].
Figure from [40].The discovery of naked diggers and some other animal species without pronounced aging has for some time led scientists to believe that aging is not a consequence of the accumulation of damage by the body, but a genetic program that, although it works in most living organisms, is still not mandatory*.

Such an optimistic view suggests that one day people will be able to find a way to turn off the aging program, which we no longer need. Some studies support the idea that with age, the body does not accumulate damage incompatible with youth.

* – In general, there are several hundred theories of aging at different levels of the organization of living matter – from molecular to population, and even with differing explanations of evolutionary patterns and mechanisms. And not all of them conflict with each other, because they can concentrate on different levels or consider aging from different angles. The phrase "accumulation of damage" is also understood differently by different groups of biologists/gerontologists, but perhaps the main logical "opponent" of the theory of programmed aging (and death) is the concept that believes that organisms - if we talk about programs – are programmed to survive rather than to die. And aging is the result of a failure of this program, associated with the effect on the body of many external and internal factors – but this already refers to other theories of aging, not programmatic. – Ed.

Firstly, back in 1958, John Gurdon managed to grow a healthy and prolific frog by adding the nucleus of the somatic cell of an adult animal to the egg [3]. As it turned out, during the life of an adult, its genetic material has not accumulated damage that would prevent the development of a healthy animal "from scratch". And, more importantly, any DNA changes – inherited or arising during the frog's lifetime – were reversed, effectively zeroing out the age of the genetic material. There is nothing unnatural in zeroing the "clock" of cells at all – after all, it happens at every conception, when two germ cells of sufficiently mature people produce a zero-age embryo.

Secondly, a number of experiments demonstrate that cells can be returned to a "younger" state if they are placed in a "younger" environment – cultured in the blood serum of a young animal or connect the circulatory systems of young and old individuals [4]. It is noteworthy that in the latter case, the studied cells of a young animal connected to the circulatory system of an old one became "older" for a number of signs. This means that the state of cells is largely determined by the environment in which they are located, and the blood and other extracellular substances of both old and young animals contain factors affecting the manifestations of age.

Finally, the invention of methods of genetic reprogramming of specialized cells into pluripotent ones inspires great optimism: after all, if it is possible to return a specialized cell to a stem cell state, there may well be a way of less fundamental reprogramming of cells that returns their "clock" not to zero, but only for some time ago [5].

Nevertheless, the optimistic concept of aging as a genetic program has some weaknesses. Firstly, it is strange to think that nature has provided the vast majority of animals with an aging program simply so that they are guaranteed not to linger in this world. Most animals do not live to old age at all, and such a mechanism of guaranteed dispatch to the next world for them looks clearly redundant. The example of naked diggers confirms that the aging program of animals is not needed either to control the number (naked diggers do not become too many due to the fact that they do not age)*, nor to enhance selection and, as a result, improve the fitness of animals (naked diggers will give anyone a head start in fitness: they, for example, have learned how to fight cancer, which other animals are still very far from) [6]. So why would most animals need such a program, without which you can easily do without?

* – In naked diggers, the population size seems to be limited mainly due to the death of young individuals (high infant mortality is normal for most species). In a colony of these animals, only one female queen reproduces, but she does it quite intensively, so it is difficult to say whether breeding "under license" limits the total number (otherwise, other birth control and settlement mechanisms would certainly work) and whether it affected the fixation of abnormally high life expectancy of diggers by selection (or maybe, was the causal relationship reversed, or is it not at all?). Anyway, diggers are mortal. And, apparently, they even age (further observations will clarify this), but in their own way - too delayed and quite atypical for mammals, without showing signs of the usual senile pathologies. Living in a protected underground environment has a long life, and a long life involves the development of mechanisms that counteract cancer and other "age-related" diseases. And the specifics of this very underground environment once determined exactly what these mechanisms should be. – Ed.

Sacrifices for the benefit of the collectiveIt is very beneficial for cells to live as part of a multicellular organism, but it is impossible without sacrifices on the part of community members.

A cell as a part of an organism cannot grow and divide uncontrollably, because in this way it risks violating the structure plan and destroying not only itself, but also colleagues in the body. Therefore, the cells of a multicellular organism are connected to a complex signal system that tells them how to live so as not to harm the community. Manifestations of the "etiquette" of the components of a multicellular organism can be observed even in cells grown on Petri dishes: when a cell touches another cell, it stops growing [7].

The absence of the telomerase enzyme in most cells of the body can also be attributed to subordination to the system of rules of living together. It is necessary to copy DNA before each cell division so that both daughter cells get hereditary material. But with each copying, the DNA molecules inevitably shorten. Most cells do not have telomerase, which restores the length of DNA after it is doubled, so they can share only a limited number of times – until the DNA of their chromosomes is shortened to a critical length. Such consent to life without telomerase, with a limited number of possible divisions, can also be considered as a sacrifice of cells of a multicellular organism for the benefit of the community.

If the system of rules for the joint life of cells is violated, tumors arise – uncontrollably dividing cells that do not care about the structure plan and who only care about their own momentary well-being. Against such sabotage, the cells of the body have protective systems: ideally, each cell should sacrifice itself if processes begin in it that can lead to malignant degeneration. For example, mutations may accidentally activate genes that provoke uncontrolled division or loss of specialization. Such suspicious processes lead to cellular aging – the stopping of the cell cycle and the manifestation of some other characteristic signs. For example, old cells secrete inflammatory factors that attract the attention of immune system cells to them. Cellular aging is a chance to correct accumulated errors, after which the cycle, generally speaking, can resume. Therefore, in the early stages, aging is reversible, including experimentally [8]. But if an aged cell does not cope with the healing of damage, it is destroyed by the cells of the immune system until it turns into a tumor and does not harm the body.

Cellular aging is a reasonable system of protection against cancer, and, as already mentioned, in naked diggers – almost non–aging rodents – this system works perfectly. It was recently discovered that naked diggers form a unique variant of a protein that stops the cell cycle during aging: it is a hybrid of two proteins that can separately perform this function, p15 and p16 [1]. The hybrid protein blocks the cell cycle of suspicious cells very quickly and effectively, giving cancer no chance. What is important is that the two proteins from the halves of which the hybrid is assembled are also being developed, and their proportions depend in a complex way on the severity of the stress to which the animal is exposed. It turns out that the cellular aging of naked diggers is not only powerful, but also flexible: the cells of these animals, thanks to complex systems of regulation of the development of different forms of cell cycle blockers, give each cell – depending on the circumstances – the right time to recover from stress.

Another feature of the cells of naked diggers is an enhanced "sense of tact" [9]. Their cells, upon contact with their neighbors, stop growing much earlier than the cells of other animals. It turns out that the naked digger is a kind of "super–multicellular", in which the systems of rules for the joint life of cells and the screening out of "scammers" – cancer cells – are brought to perfection. And this manifests itself in the launch of cellular aging wherever it is really needed.

If cellular aging is such a good defense against cancer, why haven't all animals developed such powerful and effective programs for it, like naked diggers? The answer, apparently, lies in what happens in the body after the destruction of an aged cell. In order for the organism to continue to exist in its former form, the destroyed cells must be replaced with new ones resulting from the division of stem cells. Ideally, stem cells should divide constantly, but they should not age. To do this, they have the enzyme telomerase, which maintains the length of the ends of the chromosomes, which is why their DNA does not shorten after a series of divisions. In addition, in a series of stem cell divisions, as it turned out recently, each new stem cell keeps the best cellular components for itself, throwing off its sister cell, which goes into specialization, which is worse [10]. Still, stem cells cannot be completely protected from mutations and accumulation of low-quality cellular components. As a result, they also age, albeit not in the same way as specialized cells [11]. Old stem cells retain the ability to divide, but its rate ceases to be optimal – cells divide either too rarely or, conversely, too often. In the first case, too few new cells are formed to fill the vacancies that appear after the removal of old specialized cells. And if stem cells divide too often, they do not have time to restore resources after each division and simply cease to be stem cells. Due to attempts to save stem cells and prolong your life, the aging that is aging is manifested at the level of the body.

Excesses in the operation of useful mechanismsMore and more data indicate that aging is not the result of a harmful program, but a consequence of excesses in the work of mechanisms that, with moderate activity, are beneficial.

From this angle, you can look at all the mechanisms that contribute to aging: the accumulation of reactive oxygen species, the weakening of signaling along the insulin pathway, inflammation. In small "doses", all this benefits the body, but if these processes are abused or disturbed, the effect is destructive. Moreover, not only for the cell itself, but also for the whole organism.

Reactive oxygen species (ROS) – a byproduct of the cellular respiration process – tend to react violently with everything that gets in their way. Despite this, cells that do not like to see something go to waste use these dangerous molecules as signaling. From the outside, this decision looks about as wise as the idea of using nuclear missiles to deliver mail. Fortunately, some recent scientific papers refute the first impression of the completely insane structure of living cells. Yes, ROS, even in small doses, react with everything that comes across, and cause destruction. But small destructions cause restorative responses that tone the cell and at the same time strengthen its defense against other potential dangers [12]. ROS in small doses can be compared to a vaccination, which should activate the immune system, but should not be really dangerous for the body.

And yet, when there are too many reactive oxygen species, they begin to harm. One of the first really popular theories of aging, developed in the 50s by Denham Harman, connects aging with the accumulation of ROS [13]. However, nowadays this theory in its pure form has fewer and fewer supporters. A lot of data has already been obtained that by itself a large number of reactive oxygen species does not have to lead to aging. For example, the same naked diggers form a lot of ROS, but there are no advanced protection systems against these molecules [14, 15]. Data that aging is not directly related to the amount of reactive oxygen species formed have also been obtained for other animal species [16, 17]. Nevertheless, there is no doubt that the accumulation of free radicals aggravates the condition of the cell and accelerates aging, if other factors contribute to this [18].

The situation is similar with the weakening of signal transmission along the insulin pathway, which manifests itself during the aging of animal cells of different species [19]. The molecules of the insulin pathway "sense" the amount of nutrients and signal to the cell whether it is now possible to store nutrients or whether, on the contrary, it will be necessary to spend previously accumulated. As already mentioned, with age, the activity of this pathway decreases, and the cell begins to behave as if hungry times have come – it reduces the cost of growth and synthesis and divides less actively. Since this effect manifests itself with age, one would expect that after its "inclusion", premature aging will begin in young animals. As if not so! Studies have shown that constant suppression of insulin signaling has a good effect on the condition of the animal and prolongs its life [20].

The contradiction here is only imaginary: suppression of insulin signaling is a generally useful reaction of the body, which has the same effect as limiting the caloric content of food, prolonging the life and improving the health of animals of various species. If the insulin pathway is constantly slightly suppressed, this, as well as small amounts of reactive oxygen species, has a tonic effect on the cell. And in the process of aging, this pathway is already actively suppressed – mainly in order to save stem cells and prolong the life of the body. The consequences at the organizational level are far–reaching - for example, the number of immune system cells decreases, which, in addition to fighting infections, are important for removing already aged cells [21]. Because of this, the proportion of old cells in the body increases with age, and the predisposition to diseases.

The famous mTOR pathway also focuses on the activity of the insulin pathway, which affects the rate of protein synthesis, as well as the course of the cell cycle, based on the amounts of available nutrients. mTOR inhibitors, the most famous of which is rapamycin, increase life expectancy, including healthy, in a wide variety of species of living beings [22, 23, 24, 25]. Nevertheless, it is dangerous to actively suppress such an important pathway – suffice it to recall that rapamycin was originally used as an immunosuppressor [26]. It also has other side effects: deterioration of wound healing, development of cataracts and insulin resistance, degeneration of the testes [27]. All this once again underlines the idea that there is no single harmful process that can be suppressed to end aging. The mechanisms that ultimately lead to the aging of the body are useful, but they can start working untimely or with inappropriate intensity, which is why unpleasant consequences arise. Trying to completely disable these mechanisms in order to defeat aging is too dangerous, as they are vital.

Another process accompanying aging, which is necessary in itself, but with excessive use only aggravates the situation, is inflammation. Inflammation is a way to attract the attention of the immune system to the part of the body where something went wrong – for example, an infection center appeared. To do this, the cells secrete special factors that lead to vasodilation (to make it easier for the cells of the immune system to get there), blood flow (therefore, areas of inflammation often look reddened), as well as an invasion of immune cells ready to deal with the problem. Inflammatory factors are included in the set of substances secreted into the blood by an aged cell, and the pathways associated with inflammation begin to work more actively with age [28, 11]. Although it is necessary to direct the immune system to the old cell in order to remove it as soon as possible, the excessive accumulation of such cells trying to attract attention leads to systemic inflammation – a reaction at the level of the whole organism. Against this background, many senile diseases easily arise: rheumatoid arthritis, atherosclerosis and myopathies, in which the overly raging immune system begins to destroy muscle cells. What is most interesting, increased inflammation contributes to what all these difficulties with cellular aging were conceived against – the development of cancer [29]. The mechanisms of this effect are complex and have not yet been fully investigated, but it is well known that the inflammatory environment promotes the proliferation of tumor cells. Perhaps this is due to the partial overlap of inflammatory pathways and the response pathway to steroid hormones, as a result of which tumor cells perceive inflammation as another reason to share [30].

Finally, cellular aging itself can be considered as a useful mechanism, which, nevertheless, can break down in many different places and is therefore dangerous. Indeed, it is very important to inhibit the development of cells that can potentially become tumor cells. And a slight increase in the content of protein p16 – the main effector of cellular aging – even prolongs the life of animals [31]. But if the process of cellular aging is too active, then old cells will accumulate faster than they are removed, which will lead to unpleasant changes in the environment of the whole organism. Another potential problem is that old cells will be removed quite actively, but will not be replaced with new ones, which may cause dystrophy. On the other hand, increased zeal in replacing old cells with new ones will lead to a rapid depletion of the stock of stem cells.

How to live with itThe problems leading to the aging of organisms are serious, but can be solved (Fig. 2). For example, it is possible to help the body remove cells with signs of aging so that they do not accumulate and do not release harmful factors into the bloodstream.

Recently, scientists have managed to obtain a line of mice in which cells that develop one of the main markers of aging – protein p16 – self-destructed without waiting for the appearance of immune system cells. In this straightforward way, it was possible to significantly improve the condition of mice with progeria (premature aging) [32]. Unfortunately, such experiments have not yet been performed on healthy rodents, but in general, the result of the work is encouraging and interesting.


Figure 2. Ideas for eliminating signs of aging of the body. Figure from [40].

The problem with stem cells also does not seem to be unsolvable: as already mentioned, their condition can be improved by placing them in a more "young" environment, which means that it is possible to identify factors that will help stem cells to remain young. It is also possible to improve the regenerative abilities of stem cells by inhibiting the insulin pathway and the mTOR pathway [33, 34].

Stimulation of DNA repair systems, as well as chaperone systems that correct defects in the laying of protein molecules, can help combat the accumulation of damage [35, 36]. In addition, for the timely removal of damaged proteins, it is useful to strengthen the work of the ubiquitin-proteasome protein destruction system (which, by the way, is very active in naked diggers), as well as the autophagy system of damaged organelles (the activity of which, according to some data, is promoted by sports) [37, 38, 39]. An important step on this path should be the development of ways to target the desired group of cells – because some effects will need to be applied either only to stem cells, or only to specialized ones that have already begun to age. For example, the same effect on the insulin pathway positively affects the functions of stem cells, but it would be desirable for the rest of the body's cells to be able to adequately assess how things are with nutrients. Thanks to the targeted effect only on the desired groups of cells, it will be possible to reduce the side effects of interference in the life of the body.

Another important area of work is the qualitative improvement of cellular aging systems, so that this process would take place exactly in those cells where it is needed, and with the "right" intensity. To do this, it is necessary to study in as much detail as possible the systems of regulation of cellular aging of naked diggers – animals with the most effective and flexible system of responses to a variety of types of stress. After all, it is thanks to the ability to very accurately determine which cells it is time to get rid of, as well as fast and accurate mechanisms for their removal, naked diggers manage to live their lives in a remarkably healthy state and without signs of aging at the body level. In other words, these animals do not slip into unnecessary and harmful cheating of their stem cells, because they clearly understand which cells no longer have a chance to remain normal members of the community, and they are destroyed in time. Perhaps some solutions from this system will be able to be implemented in the cells of other animal species.

Living cells have been learning to live together as part of organisms for hundreds of millions of years. With their characteristic tightness, they created communication systems from improvised means. Some components were used to solve many problems at once, which led to, on the one hand, a closer relationship of different parameters, thanks to which the cells of a multicellular organism better understand the state of the entire system, and on the other hand, some strange side effects that evolution is now difficult to unravel (for example, inflammation, triggered to eliminate old cells, promotes the development of tumors, against the formation of which cellular aging is directed). Living beings are not perfectly arranged, but not so crazy that they automatically begin to deteriorate over time, if this did not begin to happen to them for external reasons. There is no time bomb that nature places in most living beings so that they replace each other more often. There are not the most successful engineering solutions, not very accurate assessments of their own capabilities (cells that are not eliminated in time) and, of course, freeloaders trying to parasitize the community (tumor cells), with which the body must necessarily fight. All these are everyday problems, in general, in which there is nothing mystical, fatal or unsolvable.

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04.12.2015
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