General system theory of aging. Special role of the immune system

Chapter 1. Methodology and principles of studying the aging phenomenon

1.1. The main methodological errors, myths, and cliches in the general analysis of the problem of aging

The most famous and common is, apparently, a statement from which often popular, and often scientific, lectures on aging often begin.

They say that the general theory of aging does not exist, there are several hundreds of theories of aging, but none of them is true, that you need to create a “correct” theory of aging, which will indicate the unknown cause of aging and abolish aging, leading not only to eternal youth but also to immortality.

In fact, everything here is not true exactly the opposite: the theory of aging exist, it is one, it includes all existing “theories” as special cases – the mechanisms of aging, it is impossible to abolish aging as a general phenomenon of life, but also of Being as a whole, but’ eternal youth ‘does not mean immortality.

The common cause of aging is known as part of ontogenesis, part of life itself, as a phenomenon of disruptions in the structure and function of the system accumulating with age, as movements from order to chaos (Comfort, 1967; Galimov, 2006; Giaimo, 2014; Gibbs, 1928; Gompertz, 1825; Gladyshev, 2012; Hayflick, 2007; Dontsov, 1990, 1998; Dontsov, Krutko, 2009, 2012, 2016; Krut’ko et al, 2018; Nicolis, 1989).

In general, it is a natural process in nature, since it proceeds with an increase in entropy; in a particular form, this is known as the second law of thermodynamics – the accumulation of chaos in a discrete system.

But the reason is a principle, not a mechanism; it cannot be canceled (like most fundamental reasons); one can only oppose another principle (self-renewal and development).

The desired “eternal youth” would not lead to immortality, since aging is an increase in the probability of death with age, and eternal youth is only the constant (and not zero) probability of death throughout life. Such a situation would only lead to a different principle of extinction of the “ever young” population with a relatively small increase in Average life expectancy (ALE), but with a very large of psycho-social problems.

Indeed, during aging, when the probability of death increases with age by an order of magnitude, the main extinction of the population is drastically shifted to older ages, whereas with “eternal youth” the probability of death is constant throughout life and the average life expectancy (50% survival rate) sharply shifted to the left, which is typical of all systems with a constant stochastic loss of elements, for example, for the radioactive decay of elements.

From demographic data on mortality in developed countries, it is known that life expectancy in them now reaches 80—85 years or more, that is, the population is guaranteed life expectancy, which is considered by the population as personally expected, “guaranteed” duration of their own lives, about 85—90% of “Maximum” (90—100 years).

On the other hand, the “forever young” ALE would not reach even 15% of the maximum possible life span, and the absolute values of the ALE are not important here since the fundamental mortality curve depends on the principle itself – the immutability of mortality with age ((Figure 1)).

Figure 1. The probability of mortality of the population for an aging (left) and ageless (right) population. Horizontal – time (years), vertical – the percentage of survivors persons. Average life expectancy is indicated by the vertical dotted line on the horizontal time axis. The probability of mortality of the population: ageless population, for 20-year-olds 0.001% per year.

Among other myths, it should be mentioned first of all the idea that there is a Maximum life expectancy (MLE) equal to 100-120-140-170 years, etc. (depending on the personal preferences of the authors), and it can be achieved, it is enough just to study the experience and “device” of long-livers.

However, the available fixed maximum life spans are the Record life span (RLS) the exception is that the “tails” of the curves of the normal distribution of signs are impossible for any large part of the population to achieve. Such “tails” are typical for any statistical distribution and can only be oriented on the life expectancy policy. In addition, the MLE, in general, cannot exist as a definite digit: the extinction of a population is a probabilistic law (a curve, not a digit) and there is always some probability of living longer than a given limit. You can only talk about what percentage of the remaining population (and accordingly what percentage of the extinct population) is considered as the basis of the “MLE”, which should rather be interpreted as SLE (the species limit of life).

At the same time, a sharp increase in mortality with age leads to the fact that the differences between the life span of the remaining 1%, 0.1%, 0.01% and so on, the populations differ not even by years, but by months, therefore the MLE it is quite adequate to consider the life span of the life span for the remaining 1% or even 5—10% of the population

The notion that mortality is determined only by a specific cause, and by removing specific causes we remove the mortality itself, indefinitely extending the life span – the typical “myth of doctors.” This gave rise in the middle of the last century to numerous movements for general improvement. A number of longitudinal studies, however, showed that mortality in such groups, usually focused on the prevention of cardiovascular diseases, as the main cause of death, decreases very slightly, although the mortality from cardiovascular diseases itself is quite pronounced – there is a redistribution of mortality: “Compensatory phenomenon of mortality”, with increased mortality from other causes. For a gerontologist biologist, however, it is quite obvious that mortality is the result primarily of a decrease in viability, and causes of mortality are secondary: mortality does not add up as the sum of causes, but decomposes according to them, while the specific causes of death and internal super-strong effects for the body.

The concepts of the relationship between aging and evolutionary processes are widespread (Flatt, Schmidt, 2009; Giaimo, 2014; Hughes, 2010; Kirkwood, Melov, 2011). The myth that aging is evolutionarily important: like the death of old for “opening the road to the young” is a typical myth of non-specialists in the field of evolutionary theory and ecology. It has long been known, however, that in real life with very high mortality to old age, almost no wild animal survives. On the other hand, in many cases, age experience (birds, mammals) or sizes that increase constantly with age (fish) reduce (!), and do not increase, actual mortality under natural conditions. In addition, evolution can only affect the reproductive period, and the older ages are simply “not visible” to it. Evolutionary influences are important in a certain form – evolutionary found mechanisms of maximum adaptation are not required for the period of aging, and if they are important for the maturity period but have “off” or mismatch mechanisms with age and other unfavorable moments, these features will appear in old age as regulatory mechanisms aging (typically – climax).

A whole group of myths is connected with the possibilities of absolute regeneration of all structures of the body or, on the contrary, with the programmed aging and death, which leads to ideas about biological “hours of death” (Kirkwood, Melov, 2011; Afanas’ev, 2010; Olovnikov, 2005; Rando, Chang, 2012; Walker, 2011). This is usually associated with cellular self-renewal: with the fact that cells, on the one hand, have a life limit within them (Hayflick phenomenon), on the other hand, many cells are immortal in culture, and on the third side, only stem cells are immortal and only update all body tissues. In fact, everything here is not true. It has long been shown that the Hayflick phenomenon is a purely cultural phenomenon and only for a limited cell type, with which the author himself had long agreed, preferring now stochastic ideas about the nature of aging (Hayflick, 2007). Cells in culture change over time, mutate and undergo selection, so over time, it is a different culture (this is well known to practitioners who initially work with one type of cells for a long time – the results obtained on cultures of the “same” cells with different groups of scientists are contradictory).

It is known that self-renewal of cells, such as the liver, is primarily due to the liver cells themselves, and not stem cells – this is clearly seen when regenerating it in an experiment, when almost all hepatic cells can enter during the first regenerative mitosis during the day; only when such regeneration is blocked, stem cells begin to be activated in significant quantities – the so-called “oval liver cells” (Strick-Marchand et al., 2008). Stem cells are not immortal – silent stem cells eventually die for purely probabilistic reasons and mechanisms; stem cells that emerged into division form populations that are also depleted over time, some are replaced by other populations. Whether dividing stem cells can go to rest and replenish the silent pool of stem cells, and not only differentiate into more specific, highly differentiated tissue cells, remains little understood. With aging, rather, the active effects of an old organism on the stem and other cells are revealed, which can be seen in systems of syngeneic transfer between young and old animals (Albright, Makinodan, 1976; Gorskaya, 2011).

The notion that there is an “aging program” is another widespread myth (Kirkwood, Melov, 2011; Olovnikov, 2005; Rando, Chang, 2012). It is enough, however, to indicate that they ignore (or rather, do not understand or even do not know) stochastic processes, which naturally direct any systems to decay, and which do not require any special “program” for this. It is easy to understand on the basis of a mechanical analogue: a mechanical machine is created according to the drawings – “according to the program”, but when it starts to be used, the program is completed and its aging goes not according to the program, but according to the stochastic mechanism, due to the law of increasing entropy.

Thus, it is quite clearly seen that the basis of all the myths about aging is the lack of knowledge of scientific methodology and the inability to apply theoretical methods on the one hand, while inflating particulars on the other. As a result of the extreme specialization of the sciences, there are almost no scientists with a broad view – there are narrow specialists who do not see the big picture. On the other hand, there is the issuance of their own desires for scientific truth, as well as abstract reasoning for experimentally verified facts.

In questions about the cause of aging, the main mistake is a lack of understanding of the epistemological (theory of knowledge) fundamentals: the reason is not a specific mechanism, but a principle, another level of problem analysis. For the reason they give out various particular mechanisms, which leads to the “theories” of aging that grow beyond any measure and which do not “see” each other and any other mechanisms of aging.

The lack of systematic thinking does not allow us to see the problem of aging in general, and the lack of consideration of the hierarchy of the structure of the system does not allow us to see a qualitative difference in the manifestations of aging for different levels of organization of living systems.

Modern scientific analysis of the aging process should be carried out at a high level of abstraction, describing aging as a general phenomenon of the world, pointing out the most common mechanisms of aging and discovering fundamental ways of influencing them; should allow a general mathematical idea, the conclusions of which should not contradict the well-established experimental data on aging, in particular, the probability distribution of age-related mortality, and also clearly indicate the main physicochemical and biological mechanisms of aging.

Only for a man the question of prolonging life and preserving the personality, and especially the question of aging as a phenomenon of life, has become urgent. This, in particular, means that a person currently does not obey the laws of biological evolution and opens up to him purely human tasks and prospects for further development, based on the peculiarities of a human being – his intellect and psyche.

The real victory over aging means not the frozen “eternal youth”, but its further development in the physical and spiritual sense, controlled by the person himself.

For the level of all mankind – the taking under control of the biological nature of man and its further controlled development on the basis of a fundamentally new, that only man has – his mind and psyche.

1.2. History of views on the aging process

Aging of living organisms is difficult to study in the framework of a single discipline; therefore, this complex process is studied in various fields of science: biochemistry, molecular biology, genetics, demography, mathematics, medicine, and sociology (Anisimov, 2008; Atwood, Bowen, 2011; Burnet, 1970; Comfort, 1988; Babaeva, Zuev, 2007; Chebotarev, 1984; Chernilevsky, 2008; Dean, 1988; Gladyshev, 2012; Bogomolets, 1938; Gavrilov, Gavrilov, 1986; Davydovsky, 1966; Dilman, 1981; Dogel, 1922; Freitas, de Maga-lhães, 2011; Frolkis V.V., Muradjan, Fuente et al., 2011; Giaimo, 2014; Gompertz, 1825; Gorskaya et al., 2011; Harrison et al., 1982; Hayflick, 2007; Hughes, 2010; Jarygun, 2003; Khavinson, Konovalov, 2008; Khalyavkin A.V., Jashin, 2004; Kirkwood, Melov, 2011; Kishkun, 2008; 1967; Korshelt, 1925; Mechnikov, 1908, Nesterenko, 1984; Oliveira et al., 2010; Olovnikov, 2005; Rando, Chang, 2012; Semenkov et al.., 2005; Streler, 1964; 1992; Shabalin, 2005; Shmalgausen, 1926; Sohal, Orr, 2012; van Leeuwen et al., 2010; Veisman, 1914; Vojtenko, Poljuhov, 1986; Walford, 1969; Walker, 2011; Zavadsky, 1923).

General questions of the biology of aging and the specific manifestations of aging in various organisms in evolution are considered, for example, in reviews (Dean, 1988; Flatt, Schmidt, 2009; Freitas, de Magalhães, 2011; Hayflick, 2007; Hughes, 2010; Kirkwood, Melov, 2011; Masoro, Austad, 2011; Sohal, Orr, 2012; Vern et al, 2011; Walford, 1969).

The method of theoretical consideration of the issue is earlier than the experimental one, and no less important, and in some cases even the only possible way to obtain information on the most general laws, causes and essence of the phenomenon.

Gerontology studies the age dynamics of the vitality of the human body, the manifestations of aging at all hierarchical levels – from molecules and cells to organ systems and the whole organism, factors affecting viability, statistical patterns that characterize age-related changes in mortality in populations and in certain groups of the population, having certain differences related to gender, profession, ethnic characteristics, etc., as well as diagnostic methods for the aging of the whole organism and its parts and possible of life and would impact on aging with a view to slowing down and appeals.

The basis of modern scientific views on the essence of life and being in general is the doctrine of development, change, evolution, progress of all things, which, however, was known in ancient times: “Everything is in motion, everything flows, there is no rest and rest” (Heraclitus Ephesus, 480 y.).

One of the oldest explanations of the main cause of aging as a phenomenon inherent in living organisms was the study of the “life force” (Aristotle’s “entelechy”), which tends only to be wasted over time for any born organism, the beginnings of life and death. These ideas served as the basis for the development of the whole complex of theories of “wear” of the body – from Mop (1888) and Gertvig (1914), who considered that “the body wears like a machine”, to modern theories of wear their specific material substratum of this “wear” – unique genes, etc..

With the development of modern narrowly specialized science, the criticism of general notions as “idealistic” was replaced by crude materialism, which often reduces the reason, manifested as a general, to its particular specific manifestations.

Not surprisingly, as a result, all theories of aging, based on particular propositions, failed and are recognized only as a description of the mechanisms of aging, but not its root causes. It is impossible not to see the continuity between the term “life force” and the terms “vitality”, which are essential for medicine, biology and gerontology. Similarly, the dual “entelechy” corresponds to the antagonism of catabolism and anabolism, or the opposite of the systemic process of destructive aging and the opposing complex of adaptations and increase in the vitality of the organism.

Interestingly, it is the general idea of the spontaneous loss of “life-ability” that is currently the cornerstone of all scientific gerontology. This idea was, in particular, the basis of the famous B. Gomperz formula (1825), which most accurately describes the mortality of man and, apparently, of most other organisms. Gompertz also noted the similarity of curves of changes in mortality and entropy, and Perks (1932) directly wrote that “the inability to resist destruction has the same nature as energy dissipation” (that is, aging is equivalent to an increase in entropy, which serves as a measure of the disorder of any system).

The well-known biologist of aging, A. Comfort, in his famous, classic classical “Biology of Aging” (1967), explicitly states that the mysterious “entelechy” and “vitality” at the modern level of understanding can be reduced to a fairly specific, though not the real substrate – “at the present time it seems quite probable that the information contained in the cells is that” biological energy”, the existence of which was previously assumed and which was thought to be wasted with age”.

The fact that entropy for any closed system only increases in time has long been known as the most general law of Being.

Life opposes the flow of entropy, organizing a counter-flow of order, however, effective opposition is possible only if all levels of the system are updated at all levels. For this reason, life as a whole does not age but develops, but by changing all forms – organisms. The organism, being by its nature a “complete” morpho-functional object, can only grow old immediately after cessation of growth and development. This pattern was grasped by many, having formed a number of theories of aging as “continuation of development”, “end of growth and development”, “consequences of cell differentiation”, “restriction growth”, “special type of growth restriction”, etc. However, these theories lacked methodo-logical completeness – generality, which is due to the lack of an adequate language for describing general processes in general.

In biology, the whole problem of aging is closely related to a number of areas, among which traditionally stands out the theory of reversibility of life processes, which arose on the basis of the study of dedifferentiation and regeneration.

It is about the opposite (in the morphological sense) movement of the processes of development, or reduction. The experiments of L.Vudroff on the reduction of the hydra during the fasting and its new development after the fasting indirectly confirmed the possibility of directional influence on ontogenesis. The zoologist E. Schults wrote about the limitless ability of living matter to reduce and rejuvenate. In studies on the reduction of the body in experiments on planarians and other multicellular animals (1904—1908), E. Schulz believed that this would lead to the reverse development of the organism. However, in later studies of Shaksel, Driesch, Hakslee and others, it was shown that this is not quite the case.

A large series of works on rejuvenation was performed on multicellular animals with good ability to regenerate lost parts of the body. Thus, in the experiments of Korshelt (1925), periodic cutting off of a part of the body in planarians led to the regeneration of lost parts and to a 20-fold prolongation of life (from division to division). Even greater progress was achieved in experiments on unicellular animals. For example, Hartmann (1928), by means of 130 periodic amputations of the body of an amoeba, restrained her from division and thus prolonged life (without division) 65 times.

Many researchers have shown that a number of metabolic disorders and the functions of organs and systems in an aging organism are reversible, which opened the way for research on biostimulation as a separate direction in gerontology. Some preparations of cell and tissue therapy, as well as cytotoxic sera belonging to the group of biological stimulants, have high activity and the ability to slow down the aging process. In order to activate the elements of the connective tissue and the immune system, academician A.A. Bogomolets developed and introduced into the practice of medicine anti-reticular cytotoxic serum in 1938, which is successfully used to slow the aging process. Academician V.P. Filatov proposed a method for obtaining tissue therapy preparations or nonspecific biostimulants from animal and plant tissues.

Closely related to the work on biostimulation research on the effect of stress on aging. Whole theories have been developed that treat aging as “chronic stress.” However, it seems to be of greater importance here to study the mechanisms of adaptation, when stress is only one of the stages of adaptation in general. In the creation of complete theories of adaptation, an important role belongs to domestic scientists. Thus, the studies of L.Kh.Garkavi, E.K. Kvakina and M.A. Ukolova (1975, 2002), recognized in the USSR as a discovery, showed the possibility of long-term support, not activation of stress, but biostimulation. It is accompanied not only by recovery from many chronic diseases but also by obvious signs of rejuvenation. The mechanisms of these influences, the authors see in the restructuring of the body’s reactivity, and especially in improving immunity.

The important role of the immune system in aging was paid attention to for a long time, in particular, the great Russian immunologist and aging biologist I.I. Mechnikov, however, all attempts to create immune theories of aging and even to find out the specific mechanisms of the influence of immunity on aging until recent years were not consistent. This is all the more strange since the experiment has long been known that it is immunologic drugs that are the most effective geroprotectors and biostimulants, and changes in the organs of immunity (thymus) are the most demonstrative during aging.

Currently, however, Russian scientists have shown fundamentally new mechanisms of influence of immunotropic cells in the body. Studies of A.G. Babayeva awarded recognition as a discovery, showed that T-lymphocytes can directly influence the processes of cell growth and the differentiation of various cells. This was the basis for us to put forward a new immune theory of aging, which directly links involution with the age of the immune system and a sharp decline in cellular self-renewal in tissues with dividing cells (skin, mucous, parenchymal organs). These studies also give hope to use a wide class of immuno-pharmacological agents for the prevention and treatment of aging, which has been empirically proposed for a long time as many bio-activators that simultaneously increase the level of the body’s immune defense.

In the last 20—30 years, a great number of researchers worked in the field of gerontology – specialists from very different fields, including physicists, chemists, and others.

Studies by academician N.M. Emanuel marked the beginning of the development of antioxidants for the prevention of aging and bio-stimulation. A modern, extensive complex of creams and other skin care products practically does not do without substances of this group, as well as programs for the prevention of age-related diseases.

Modern anti-aging creams also include liposomes – the result of modern research on the theory and practice of artificial membranes, as well as hyaluronic acid and collagen – the result of traditional research on the aging of connective tissue of a large group of domestic and foreign scientists.

Modern studies on biorhythmology and methods of restoring and harmonizing biorhythms are undoubtedly related to the most ancient practices of acupuncture therapy in China. Modern electroacupuncture methods have proven their effectiveness (“longevity point”, etc.) and are waiting for wider use for the purposes of biostimulation and prolonging life.

Unfortunately, a large number of works claiming to discover the “fundamental causes and mechanisms” of aging, now have a purely historical interest. In many cases, these works only confused the essence of the issue, as they were based on particular issues, strengthening them to the general.

So, in fact, all theories that take the main role in aging chemical changes – the “spoilage” of proteins, DNA, colloids, etc. under the influence of cross-links, oxygen, etc., do not take into account the main feature of the living – self-renewal of the organism and cells and cannot explain the accumulation such changes over time.

Similarly, they did not give much either to practice or the theory of gerontologic and general conclusions not related to examining the organism in all its complexity: Rubner’s theory, which asserted that the amount of energy processed throughout one kilogram of body weight of different animals equally; theories about the “life hours” and the spending of the “life element” – the enzyme (I.I. Schmalhausen), the gene (L. Scillard), germplasm, differentiated cells and other material non-aging substrate; theories about the origin of aging in evolution as an adaptive mechanism (including the Weismann theory), ignoring the obvious fact of the overwhelming death of wild animals at a young age; general theories about the relationship of aging and development, reducing aging to a specific aging program, including the “death genes” or the programmed number of divisions for each cell (Hayflick’s theory), etc.; Carrel’s observations, pointing to the “immortality” of dividing cells and not taking into account the principle difference between population cellular phenomena and processes in the whole organism; Minot’s ideas, which associate cell differentiation with their death, but ignoring intracellular self-renewal, allowing non-fissile neurocytes to live throughout the whole organism and regulatetorus influences that sharply suppress potential-dividing cells, as well as many other ancient and modern theories. In general, it can be seen that research on the study of specific mechanisms of aging, very extensive and diverse, in most cases quite successfully led to the creation of various methods and means of biostimulation and prevention of individual manifestations of aging.

However, all the claims of researchers of this type to the creation of general theories of aging turned out to be completely untenable. This is not surprising since it is not methodologically correct to reduce the general laws and principles (namely, at this level, the analysis of the essence and cause of aging should be carried out) to separate mechanisms and manifestations – to particular aspects of the complex and diverse phenomenon of aging. The extreme specialization of modern scientists, which has led to just such a result, in recent years has finally been realized that it has stimulated the development of general methods of analysis – the theory of systems, self-organization, cybernetics, synergetics, etc. allow you to see the features of a common single natural theory of aging, to the creation of which all scientists aspired. The rapid development of statistics and demography somewhat overshadowed by the biology of aging, the achievements obtained by specialists in life expectancy biology. Thus, data from radiobiology, largely based on an analysis of the survival rate of irradiated animals, showed the possibility of accelerating natural aging – this is practically the only method that makes it possible to simulate accelerated aging adequate to the natural one. An analysis of historical mortality data allowed us to detect the phenomenon of the historical stability of the age-related component of mortality with a sharp decrease in the background or “external medium” component of mortality, which indicates the possibility of a sharp decrease in mortality due to socio-preventive measures, but denies the possibility of influencing in this way essentially, on the essential, internal processes of aging for the body (Dontsov, 2019).

Comparison of the age-related component of mortality for different regions of the World showed that although for each region they are historically stable, they differ for different regions.

It was mathematics that long ago resolved the dispute about the Maximum life span, as biologists believed, the “ultimate survival age” for organisms, replacing the absolute limit with the probabilistic survival law, as well as radically changing the notion of hereditary longevity, the ability to increase the Maximum life span with disease does not match the essence of aging, etc.