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

1.3. Methodology of knowledge: three stages, three paradigms

The presence of hundreds of theories of aging to date indicates not only and not so much the lack of a unified theory, general views, or lack of knowledge of the causes and essence of aging, but often a methodological lack of understanding of the subject matter. Although many gerontologists understood the importance of general biological laws (Bogomolets, 1938; Comfort, 1967; Dilman, 1981; Dogel, 1922; Frolkis V.V., Muradjan, 1992; Korshelt, 1925; Streler, 1964; Shmalgausen, 1926; Nagorny A.V., Nikitin V.N., Bulankin, 1963; Vojtenko, Poljuhov, 1986; Zavadsky, 1923), the main attention was drawn to the study of specific mechanisms of aging, issued as a reason. Science in historical development has gone through three stages, and each is characterized by its own general paradigm.

The first stage is determinism, which has received its maximum expression, apparently, in Laplace. According to his extreme ideas, know-ledge of the initial conditions uniquely determines everything that follows: knowledge of the initial coordinates and momentum of all particles at the Beginning of the World uniquely determines its picture to the present moment and the future of the World. The main disadvantage of this methodical approach is the mechanism: everything is predetermined by initial conditions, there is no freedom, in fact, there is no place for life, feeling, intelligence, free will and the whole diversity of the real World.

The subsequent development of science has changed this view of the opposite. The stochastic vision of the World, most pronounced in probability theory and quantum mechanics, was based on the recognition of a physical law stating that it is impossible to simultaneously and accurately determine the coordinate and momentum – the uncertainty principle in quantum physics. However, the proliferation of global stochasticity as a method from the micro level to the level of complex objects led to another extreme – the general unpredictability of phenomena, which also does not correspond to the state of things.

The development of a systems approach brought science out of a methodological crisis, while not discarding what has been achieved. Already one enumeration of its characteristic features, shown below, shows the enormous potential possibilities of a systematic approach – a new, whole world view (Checkland, 1986; Wolfram, 2002, etc.).

1.4. Features of the system approach as a modern universal scientific method of problem analysis

1.4.1. Using a systematic approach to analyze оf aging process

Already a short review of the system analysis requirements for the aging phenomenon makes it possible to see a number of crucially important points for analyzing the problem.

The principle of unity of the whole requires that a certain integral self-sufficient system be put in the basis of consideration. This means that the full consideration of aging is possible only for the level of the whole organism. Indeed, at the level of populations, the very concept of aging is blurred, as at the level of cells and molecules, when you can get a variety of cultural phenomena and interpret them in an arbitrary way. The importance of the principle of integrity, unity of the organism as a system is also clearly seen in the first experience of heart transplantation: in a couple of years the transplanted young heart was not much different from the old one: aging was directed by the whole organism, and the young part could not preserve its youth in the old organism. The same applies to the transfer of young stem cells to the old organism and vice versa: old cells retain their potencies and can manifest them in a young organism, while young cells reduce their abilities in the old organism (Albright., Makinodan,1976; Gorskaya et al., 2011) – the determining role of the microenvironment and external influences on the state of cells.

Considering the reality of universal interrelationships is all the more important since aging is a long-lasting process. At the same time, small changes and “side” for the main consideration of the reaction are decisive. So, besides the reactions directed by enzymes studied in biochemistry, all possible physicochemical processes in biological systems actually take place, which forms the basis of the aging processes in the form of “contamination” with secondary metabolites. Similarly, the universality of interrelations means a really huge number of influences on a real-life system and determines its fundamental vulnerability: the mortality of a particular system cannot be zero and even an “eternally young” organism will not be immortal – the stochastic mechanism of mortality. The same, when applied to specific internal structures, reveals the stochastic mechanism of system aging.

The idea that parts of a whole are not separate entities, but units of division of a fundamentally different type (entity-in-relationship) allows us to apply analysis methods at the abstract level and consider the real structure by considering the essential relationships of structural parts, which also applies to weakly structured systems (for example, metabolism for living organisms).

The most important position on the transition from the analysis of equilibrium states to the analysis of nonequilibrium, irreversible states (super) complex systems allows us to understand the fundamental unidirectionality of the aging phenomenon, to look for the presence of fundamentally irreducible phenomena that determine movement in one direction only.

The position of the system analysis that there is no entity, meaning and structure of an object outside of evolution, requires to consider the entire period of ontogenesis as a single whole, and not aging as a process that is separated from the development of the whole organism, needs to look for an association of aging with processes of growth and development of the body. In addition, the evolution of the living provides a vivid example of the evolution of the forms of aging and the possibilities of influencing it, as well as the dependence of such forms and influences on the specific structure of the living system of one or another level of complexity.

The principle of the consideration hierarchy actually reflects the different level of the real structure of the object, the presence of separate organs and systems with a special structure and function, which determines its particular mechanisms of aging for molecules, cells, organs, systems of the body and the whole organism with its common regulatory systems.

Finally, it is important to understand the essence of the phenomenon, which is considered as an ideal law that determines the appearance of the phenomenon, its functioning and evolution in the hierarchy of interrelationships of the whole.

This idea makes it possible to move away from considering the many specific mechanisms of aging to its cause, as an ideal principle and the essence of aging, and also to understand how the general principle is implemented by specific mechanisms. This is one of the stumbling blocks in modern gerontology, in which many open mechanisms of aging are given for a reason, which has already spawned hundreds of “theories” of aging.

The sticking point remains the question of the cause and nature of the phenomenon of aging, also solved by system analysis.

1.4.2. General methodology about the cause of phenomena

When one speaks of a single natural theory of aging, it is quite clear that it must answer a number of central questions:

– the time of appearance of aging in evolution;

– whether aging is a general law of nature or a private mechanism for the existence of individual forms of the living;

– what are the essence and the fundamental, common cause of aging;

– what are the general laws and particular types and mechanisms of the manifestation of aging;

– what are the fundamental features of human aging;

– what are the general perspectives and ways to overcome aging as a natural phenomenon;

– what are the specific approaches to the effects on the main types and mechanisms of aging;

– the importance of aging in general, the general way to overcome it, and the peculiarities of this task in humans.

One of the central issues in the consideration of aging as a global phenomenon is the question of the primary cause and the deep, fundamental nature of aging.

Regarding the general methodology for the consideration of the issue, it should be said that it was known in ancient times – Platon developed it in the most complete form. The leading contemporary philosopher-methodologist A.F. Losev formulates the most important provisions for us as follows: “Current experience gives us an idea only of flowing and scattered bodies and events, in which neither beginning nor end is seen and whose meaning remains vague due to its fluidity, very often incomprehensible and blind… And since the scientific understanding of a thing requires the final disclosure of its meaning, then the theory of ideas arises as ultimately developed communities.”. A full-fledged scientific analysis is characterized as follows: “To understand and correct components is necessary through the whole… The idea is the ultimate community, has a structure and is meaningfully filled, respectively has it’s own specific (own) … already purely ideal objectivity and reality… this limiting community manifests itself in its particular, in a semantic way, never moving beyond its limits… The essence (of something) is interpreted as a principle of structure…”.

Thus, it is clear that the essence, the cause of aging can be expressed only in the language of high-level abstraction as an objective pattern of life, being, as a principle, but not at all as a process, much less as a specific special mechanism in the body. The reduction of principles to mechanisms is the main methodological error in the natural sciences, including in gerontology. It is quite clear that when defining the term “aging”, the definition of the principle of aging as a phenomenon turns out to be necessary and sufficient, which has been known and understood for a long time: aging is a decrease in viability with age, or an increase in the probability of death with time, or, more, in general terms, it can be said that aging is an increase in the degree of chaos at all structural levels of the organism, which is manifested by a general decrease in the body’s resistance to all factors and is recorded as an increase in the probability of death from all causes of aging.

The definition reveals the very essence of the phenomenon of aging, which acts as a global, fundamental cause of aging because the cause of the accumulation of chaos (entropy) in closed systems has long been known: it is a law of nature, known in particular as the second law of thermo-dynamics. Now the interpretation of this law has significantly expanded and deepened in connection with its extension to information processes.

In biology and mathematics, the most interesting are modern trends: theories of self-organization, theories of open systems, describing the generation of information, its relationship with chaos, the role of energy in this process, etc.

The applicability of the second law of thermodynamics to living systems is related to the fact that they are only partially open systems: in any modern complex organism, there are structures that are not updated inside the organism – cells, molecules, organelles, organs, etc. Thus, the fundamental reason for the aging of any complex systems is the discreteness of the forms of existence of modern organisms on Earth – separation from the external environment, which puts a limit on the capacity for the internal evolution of an organism while preserving its quality as a separate system. In general, this is known as the inevitability of the accumulation of chaos in any partially open system limited from the external environment with time.

The self-renewability of a living system within itself is not a sufficient factor in counteracting aging in general, since it is possible to counteract the second law of thermodynamics only due to external influences on the system and these influences essentially lead to evolution, and not to stabilize any system.

1.4.3. Aging Hierarchy

The most important approach to the analysis in a systemic examination is to take into account the hierarchy of the structures of real complex systems. At the same time, system analysis requires consideration of principles characteristic of each hierarchical level.

Such a hierarchy of consideration in system analysis reflects not the material structure of the object that morphological sciences study, but a hierarchy of essential principles reflecting the laws of functioning and communication within and between the structural levels of the object being considered, which acts as a complex hierarchical dynamic system.

The following table gives an idea of the hierarchy of aging in terms of a systematic approach (Table 1).

Table 1. The hierarchy of consideration of aging in terms of a systematic approach

Three hierarchical levels of aging description are fundamentally ideal and are available only for theoretical analysis.

The last level is structural and its study is possible only when it is filled with biological content. With this consideration, it can be seen that the primary cause, as a principle, is manifested by several of the most common patterns – the types of aging inherent in all living systems. These types, in turn, form a number of interrelated groups of symptoms – aging syndromes, which already include specific manifestations of aging at the level of specific mechanisms that implement aging depending on specific conditions.

The systematic consideration of aging is also manifested in the fact that in each specific manifestation, the mechanism of aging, you can see all four levels mentioned above: a reflection of the ideal cause in specific conditions; relation to a greater extent to a certain type of aging; regular relationship at the level of mechanisms with other symptoms (syndromes); and, finally, the actual concrete actual manifestation of aging for the phenomenon under study in a specific case for a specific structure. Naturally, the more specific and narrow the phenomenon we study, the more specific, but more narrowly, the cause of aging manifests itself.

For the whole organism, aging as a whole can be sufficiently fully characterized only with the use of all four hierarchical levels of its presentation. An important and traditional is the structural consideration of the body or its individual elements.

Here again, the system approach allows revealing the moments obscured by usual consideration.

The dynamic view of the phenomenon under consideration indicates that living systems exist only as a stream, where continuity is preserved, but not always the entire real material structure. Processes in a living system occur at different time levels. So, at the metabolic level, these are (micro) seconds of biochemical reactions during which specific molecules exist; for cells, these are hours and days during which they are divided (cell cycle); for the whole organism, these are years, decades and even centuries.

Each level can have representation at a higher level with some of its structural elements (non-updated genes – at the cell level, non-dividing cells – at the suborgan level, etc.), then these lower-level elements become important for higher-level aging.

Each level is updated at the expense of a higher level, which reduces the absolute significance of the lowest level for aging higher (for example, cell growth and division sharply reduce the importance of aging or damage at the molecular level).

Each level is qualitatively different in structure and principles of organization and functioning.

All levels constitute a single whole, its change, in the final analysis, is only important as the aging of the organism is the aging of the whole.

Thus, consideration of the system analysis requirements for the aging phenomenon makes it possible to see the fundamentally important points of the problem analysis.

The most important is the ability to solve a number of central problems in gerontology in general, which allows to determine the common cause of aging systems and biological systems in particular, the main mechanisms for the manifestation of the common cause of aging, as well as the ways of manifestation of these common mechanisms of aging.

It is possible to identify the main properties of the biological system, which lead directly to its aging, to evaluate ways of influencing the aging of the organism and individual organs, systems, tissues and cells, as well as to clearly understand the prospects for such effects, their points of application and possible efficiency, as well as the fundamental The limited nature of these or other effects, the limits of their application and the ability to influence the aging of the whole organism.

The use of systems analysis puts gerontology as a science of aging on a clear methodological basis, leads it away from many circulating myths that are now replacing the general picture of aging and clear scientific views on it in gerontology.

System analysis in the first place allows you to move from the infinite consideration of particular views and mechanisms of aging to the consideration of the laws and principles that act during the aging of living systems, which just determines both the fundamentally possible main mechanisms of aging and the possible effects on it as well as the ultimate perspectives of such opportunities.

Thus, the use of the provisions of system analysis allows us to understand much in the problem of aging already at the level of abstract analysis.

1.5. Essential modeling – the basis of understanding the phenomenon of aging

The creation of theoretical models of the process under study is the most important element of knowledge, therefore this issue is given central attention in any modern field of science.

Gerontology in this regard is experiencing a crisis related to the fact that the old principles of creating conceptual models of aging, essentially reducing to the absolutization of certain observable phenomena and particular mechanisms of aging, have collapsed. All the so-called theories of aging, which now number hundreds already, have proved to be untenable in explaining the fundamental basis of aging and in many respects are only of historical interest.

On the other hand, a number of purely mathematical approaches to the modeling of aging does not meet with interest and recognition among biologists, since even with the most superficial study one can see biologically unjustified and in fact incorrect initial prerequisites of the models.

So, for example, fashionable environmental and evolutionary mathematical theories of aging, based on the idea of “expediency of aging” as a mechanism for the accelerated renewal of the species, ignore the obvious fact of high natural mortality in the wild when old animals are virtually absent in the population and almost all animals die young.

At the same time, there is an urgent need for a clear general view of the phenomenon of aging in general, using models that allow one to quantitatively and meaningfully interpret the aging of organisms. At present, one of the most important tasks of gerontology is the rather detailed development of essential models of aging, reflecting the very essence of this common to all living phenomenon and being biologically based and biologically meaningful.

Essential models must meet the following requirements:

– a clear understanding of the biological content of each element being modeled;

– a clear understanding of the biological significance of the results obtained in the simulation;

– a clear idea of the place of the model in the system hierarchy of aging processes (which part of the more general process is described);

– consideration of external factors that fundamentally affect the process being modeled.