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

Chapter 2. Theoretical approaches to the study of aging phenomenon

2.1. Essential definition and cause of aging

The essence of anything in philosophy is interpreted as the principle of structure. Thus, the essence or the essential, the main reason for aging can be expressed only in the language of high-level abstraction as an objective pattern of life, General Being, as a principle, but not at all as a process, much less as a specific special mechanism in the body. Such an essential definition of a global phenomenon, Aging has been known since antiquity – as a reduction in vitality with age. The current general definition of aging as a reduction in overall vitality with age actually does not differ from this in any way.

This definition is necessary and sufficient for a quantitative description of aging and clarification of the causes and main mechanisms of the aging process of organisms and its systems.

In its most general form, viability is the maintenance of structure and function – that is, the preservation of the identity (information) of a complex system (organism) over time.

The spontaneous direction of information change with time is closely connected in the global sense with the most general law of Being – the law of increasing entropy. Entropy and information are related, as is well known, by the following formula (1):

E = A * LnW + B, (1)

where E is entropy, W is the probability of an event, A and B are coefficients.

That is, the “natural” probability of the direction of (bio) chemical (and any!) events in time leads to the achievement of chaos as the most probable event (no longer changing), which is known as the 2-nd law of thermodynamics. The mechanism of such a path (the global mechanism of entropy) is a random process.

It is known that resist chaos can only be an external flow of energy. This flow of energy is a metabolism that forms the very basis of life as a biological form of existence of matter.

2.2. Chaos and order processes, entropy and energy

Entropy and external energy are two opposing forces, responsible both for destruction and for self-organization and change of separate, both simple and most complex systems, including organisms. Most fully these processes are considered in this section of science, as thermodynamics. Its application is possible in the study of idealized equilibrium systems, as well as in the study of real quasi-isolated or quasi-closed systems and quasi-equilibrium processes. In addition, it may be applicable when studying the processes occurring in complex open systems. It is important to understand that in reality, in any system, all possible processes actually take place, which are real and should be considered when it comes to very long periods of time and very complex systems. System analysis, as a modern scientific methodology, is precisely capable of doing this.

The processes of chaos, together with the arrival of external energy, form the whole multitude of nonlinear, developing, dynamic self-organizing systems of the most diverse nature – physical, chemical, and biological. Even B. Gomperts (1825) noted the similarity of the curves of changes in mortality and entropy. It has long been clear 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), and the well-known biologist of aging A. Comfort directly writes that “Entelechy” and “vitality” are information contained in a cell, which is “biological energy”.

The relationship of order and chaos can be represented in the form of a general scheme, reflected in Figure 2.

Figure 2. The relationship between the processes of order and chaos.

In general, the processes of disintegration of any system are guided by the law of increasing entropy in the course of naturally occurring processes, which leads to an increase in chaos and a decrease in order in the system. The only way to resist the processes of entropy accumulation is external energy. External energy is necessary to obtain an order from chaos, but it operates under specific conditions, according to a specific plan, based on information from biological systems (development based on the organism’s genetics), and by self-copying of existing biomolecules and biostructures.

The order (structure) of the system spontaneously (according to the law of increasing entropy) turns into chaos. This is opposed by the external energy, based on information (internal to the biological system) restoring the order (structure) of the system (by self-copying). Entropia also distorts this process, leading to errors. Errors of the (self) recovery of the system are controlled by selection: external and internal (by the immune system, etc.). The result is a constant dynamic process that ensures not only the constant preservation of the system, but its dynamic equilibrium and, if necessary, evolution.

Entropy counteracts this process through errors that inevitably manifest themselves at all and at all levels of system organization. Errors are confronted by selection (natural selection for the species and the immune and other mechanisms inside the body), however, the selection is also subject to inevitable errors and provides only material for the evolution of the system (organism).

In practice, it is impossible to achieve infinite evolution and complication within the organism, as is the case for species and the entire biosphere. In addition, due to the very existence of the organism as a separate system, the organism is fundamentally mortal, and selection and evolution do not have enough time and necessity (as well as opportunities) to form an ageless organism in which all errors are fully compensated inside it and full evolution and further infinite development occur. In fact, the inevitable accumulation of errors, cessation of development and reduction of orderliness in general, which is the aging of living organisms. The most important general point is that the very existence of the system is not stationarity and immutability, but a dynamic process that is in equilibrium with the external environment.

The decrease in the general metabolism known with age, the decrease in the reactivity and stability of the organism can be interpreted unambiguously as a decrease in the “openness” of the system, its renewability, and connection with the external environment. At the biochemical level, an increase in entropy is also manifested in a decrease in the orderliness of the network of metabolism, a decrease in the level of exchange of macromolecules (DNA repair in the first place), the accumulation of “errors” (including mutations), a decrease in “active protoplasm”, etc.

A reduction in “active protoplasm” can be clearly measured as the degree of sclerosis and calcium accumulation in tissues, as a decrease in tissue respiration and the level of protein and DNA synthesis, as well as by the content of total and intracellular water and by the level of bound water – the degree of hydration of molecules, etc.

Thus, it can be seen that the general concepts of entropy as a very abstract indicator directly result in a whole series of manifestations, the meaning of which age changes can be clearly understood only taking into account the theoretical concepts of the essence, meaning and general cause of the aging phenomenon.

Repair of both inanimate and living systems is possible and really happens in a unique way – by replacing old structures with new ones. In organisms, all levels of their organization are updated: at the molecular level (metabolism); at the intracellular level, subcellular structures; at the level of cell populations – cell division; at the level of supra-cellular populations (nephrons, alveoli, etc.); at the level of regeneration of organs and tissues (regeneration itself – axolotl tail, etc.).

The higher the level of structure and organization, the less the possibility of full recovery. There are completely non-renewable (except for metabolism) organisms, for example, Drosophila, which, being postmitotic organisms, do not have dividing cells, their lifespan is determined and very small, aging as a process is expressed and occurs entirely in stochastic whose type is random cell death and supra-cellular structures. In contrast, there are fully renewed organisms: the hydra has no non-renewable cells, their aging is not pronounced, and the life expectancy is not determined.

2.3. The basic formula and the basic law of aging

The first mathematical model of aging was created almost 200 years ago by B. Gompertz (1825) and still most accurately describes the age dynamics of human mortality and, apparently, of most other organisms. As a specialist in life insurance, Gompertz theoretically derived the practically necessary formula for increasing his mortality rate with age, which until now has been the most common quantitative description of aging itself.

Mortality, as “quantitative characterization of the inability to resist destruction,” can now be viewed as the reciprocal of vitality – the ability to withstand the totality of destructive processes.

A simple assumption about the stochasticity of the aging process is enough: the viability over time decreases in proportion to itself at each time point (formula 2) in order to obtain the basic law of aging: mortality increases with age by the exponent (formula 3). Such a nonspecific increase in the body’s vulnerability to all influences with age is called aging itself.

d X / d t = – k X, (2)

where k is a coefficient, X is viability, t is time.

Considering the mortality (μ) as an inverse viability value (μ = 1 / X), the basic formula (3) is obtained from formula (2) aging (B. Gompertz and W. Makekem) – with age, the overall mortality increases exponentially:

μ = Ro exp (α t) + A, (3)

where Ro is the initial mortality rate, α is the rate of increase in mortality, A is the coefficient characterizing the contribution of external influences to mortality, the effect of which weakly depends on age.

The approach to writing formula is now theoretically clear: it is an elementary differential equation that describes, for example, radioactive decay in physics and other simple probabilistic processes. The essence of the phenomenon lies in the fact that at each moment in time the state change does not depend on the prehistory, but only on the present state of the system.

The general mechanisms of such processes are also clear – these are principally probabilistic regularities associated with the ultimate stability of any elements delimited from the external environment; then a complex organism consisting of such elementary units can only lose them over time. The main issue is then the nature of such “elementary units of life.”

Gomperz himself noted the similarity of the curves of changes in mortality and entropy, and V. 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 disorder any system); A. Comfort (1967) writes that viability can be reduced to a rather specific, though not material, substrate – information in cells, which is “just biological energy”.

Thus, the meaningful interpretation of the concept of “viability” was reduced from the very beginning, and is reduced now, not so much to the material content, but to the energy and information content – to the “entelechy” of the ancients.

For a population of animals or a human cohort, by definition:

μ = dN (t) / N (t),

where N (t) is the number of members of an endangered population at time t. By integrating the Gompertz-Makema equation, one can obtain a direct formula for calculating the number of survivors of a certain age (formula 4):

N (t) =N_oexp ((-A t – R_o/α (exp (α t) – 1)) (4)

The qualitative view of the survival, mortality and survival curves corresponding to the formulas presented above corresponds to the real survival curves of various human populations, as well as a number of other species. However, the Gompertz-Makema formula describes only the middle part of the mortality intensity curve, whereas the initial part of the curve (growth and development processes – up to 20—25 years) and the final part (older than 80—90 years, individuals with hereditary longevity) cannot be taken into account in this way.

The full mortality curve, which takes into account the period of growth and development and hereditary longevity, can be obtained from the systemic stochastic-regulatory theory of aging discussed below and proposed by us earlier (Dontsov, 1990, 2012, 2017).

The general reason for allowing entropy to work in any system is the principle delimitation of this system from the external one, which does not allow it to fully renew itself and puts a limit to its existence as a separate system.

Similarly, the global cause of aging is the discreteness of the existence of life in the form of individual forms – living organisms, their fundamental limitations (limits of adaptation of all homeostasis mechanisms) in comparison with the almost infinite variety of influences on each particular organism of the rest of the World. The quantitative and qualitative infinity of the effects of the World on a discrete organism can only partially be compensated by homeostasis, which leads to the accumulation of uncompensated damage – the most common mechanism of aging.

Self-renewal of an organism at all its levels is not a sufficient anti-aging factor since the self-renewal process itself is not absolute and has the same random mechanisms.

Some obvious and experimentally and demographically confirmed conclusions are interesting, however, sometimes paradoxically sounding. So from the above, it is obvious that the greatest absolute decrease in viability can be observed at an early age, which we can see from the curves of changes in the ontogenesis of the absolute value of many physiological functions. This means that prevention of aging should begin at the earliest ages. At the same time, in old age, even small absolute changes in viability lead to pronounced changes in mortality, so at older ages, it is convenient to study the effects of adaptogens and biostimulants, although a small vital resource may not lead to a significant increase in life expectancy.

The mathematical analysis of the theories of aging, based on the modeling of its essence – the age-related decline in overall viability, turned out to be surprisingly fruitful and suitable both for objectives of theoretical research and for practical research in population gerontology. At the same time, the common cause of aging is manifested by some general mechanisms that should be modeled and evaluated for their contribution to the overall aging of the system.

Another approach to the quantitative assessment of aging, based on the same definition – reducing overall viability with age, is to consider the overall viability of the system as an integral of the viability of its parts, which, as applied to the body, means that the overall viability of the body consists of maintaining vitality (functional resource) of its main organs and systems (formula 5).

Х = k₁ х₁ + k₂ х₂ +….+k_n х_n (5)

where k is the coefficient, x1 … n is the viability of organs and systems.

The definition of individual aging as a biological age is based on this.

2.4. Basic global mechanisms: types of aging

2.4.1. The main common mechanisms are types of aging

System analysis allows us to consider aging from several global points of view, thereby revealing the fundamental, general, global mechanisms or types of aging, as a reflection of fundamentally unidirectional common processes of aging.

Although the specific mechanisms of aging for different types of tissues and organisms can be quite different, all of them can be grouped into 2 groups that are essentially homogeneous according to the global mechanism, resulting from the global cause of aging – the law of increasing entropy in some incompletely open systems, and also from counteraction by biological systems – processes of regulation of growth and development of a biosystem.

Existing theories of aging focus on several hundred specific mechanisms of aging. However, attentive analysis of these mechanisms and essential modeling of the aging process ((Dontsov, 1990; 2011; 2017; Gompertz, 1825; Hayflick, 2007; Murphy, Partridge, 2008; Vern et al., 2009: van Leeuwen et al., 2010; Walker, 2011; Kirkwood, Melov, 2011; Masoro, Austad, 2011; Rando, Chang, 2012), as well as consideration of the aging phenomenon given in previous publications, allow us to group these mechanisms into a small number of classes – general aging mechanisms and in general can only be theoretically reduced to stochastic and regulatory types of aging, while for biological systems the stochastic type appears as a probabilistic death of non-renewable elements, as well as a “contamination” of the system by external intoxes ikantami and internal metabolites.

Thus, if there is one common cause of aging, there are 2 types of aging and 3 main, fundamental mechanisms of aging.

2.4.2. Stochastic dependent death non-elements of the system

A fully formed organism has many non-updated elements at all its hierarchical levels: unique genes, non-dividing cells (for example, nerve cells, including autonomic control centers), non-regenerating structures of organs (alveoli, nephrons, etc.), organs themselves and etc.

The loss of these elements with age is probabilistic, and therefore in the simplest case, it is described by the same type of formula as the loss of overall viability:

dX / dt = -k * X,

where X is the number of non-updated elements of the body.

Graphs of total aging (mortality) for Gompertz and mortality associated with a decrease in viability due to the loss of non-renewable elements, therefore, should coincide and is exponent.

It is known that the loss of alveoli, nephrons with age, reaches 50%, and that of nerve cells in the hypothalamic regulatory centers – 80% (which links this mechanism with the regulatory mechanism of aging). In nature, the stochastic mechanism of aging is fully realized in postmitotic animals (for example, in Drosophila), in which there are practically only non-updated structural units.

The death of elements is the extreme expression of the mechanism mentioned, which, in general terms, leads to changes in the elements of any system. With age, individual structures in the body can not only die, but also change due to accumulating micro- and macro- damage, or change the structure and function of adaptation.

Due to the non-ideal selection mechanisms and self-renewal of such structures in the body, these structures accumulate with age (increase in the number of old, incapacitated cells in all organs and tissues, degeneration, accumulation of mutations in the genome, decrease in the number and quality of sperm cells, accumulation of sclerotic elements in tissues, etc.); the functions of such structures are usually reduced. The accumulation of damaged elements is probabilistic in nature; therefore, the decrease in the number of normal, intact elements with age is described by the same type of formula as the Gompertz formula for loss of general viability.

The main role in the elimination of damage is played by the mechanism of cell division, therefore the deterioration of this process manifests itself morphologically in the form of a wide variety of tissue changes – changes in the forms and sizes of subunits, atrophy, hypertrophy of functional tissue, replacement with nonfunctional connective tissue elements, etc. This is the basis of an increase in morphological (and functional) diversity at the tissue level observed with age and a decrease in their functions. This mechanism underlies such a typical aging phenomenon as atrophy of tissues consisting of constantly self-renewing cells (for example, skin).