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Biology Bullettin. THEORETICAL BIOLOGY. Thermodynamics of Aging


HomepageINSTITUTE of Physico-Chemical Problems of EvolutionBiological Evolution and AgingBiology Bullettin. THEORETICAL BIOLOGY. Thermodynamics of Aging

G.P.Gladyshev
Semenov Institute of Chemical Physics, Russian Academy of Sciences, ul. Kosygina, 4, Moscow, 117977 Russia
Received October 14, 1997

Biology Bullettin. Vol. 25, No.. 5, 1998, pp. 433-441. Translated from Izvestiya Akademii Nauk, Seriya Biologicheskaya, No. 5, 1998, pp. 533-543. Original Russian Text Copyright © 1998 by Gladyshev.

Abstract—The findings of macrothermodynamics (supramolecular thermodynamics) of quasi-closed systems and the published data on the variation of the chemical composition of living organisms in ontogeny confirm the thermodynamic tendency of aging processes. According to the thermodynamic theory, the specific value of the Gibbs function of the formation of supramolecular structures of the organism tends to a minimum. This tendency explains the variation of supramolecular and chemical composition and the morphology of tissues during aging. Thermodynamic theory makes it possible to define the principles upon which proper diets and medications can be devised to slow down aging. Such diets and medications are also useful in preventative care and in the treatment of various pathologies, including those related to old age. The chemical stability of the supramolecular structures of tissues makes it possible to understand the causes of the essentially continuous evolution of the biological world from the perspective of the second law of thermodynamics.

THERMODYNAMIC THEORY OF AGING
There are many theories of aging, most of which deal with the process mechanism. These theories concentrate on the kinetics (dynamics) of the phenomenon. As a rule, each of them focuses on changes in organisms that accompany aging. It is clear that, in general, these changes cannot be considered the cause (driving force) of aging. These kinetic theories have been extensively discussed (Advances ..., 1996; Klatz and Goldman, 1996; The Science ..., 1996; The Yearbook ..., 1997).

Another group of theories deals with the kinetic-thermodynamic aspects of ontogenesis. Most of these theories use models that consider the changes in entropy production during aging (Lee and Hershey, 1990), which are based on the works of I.Prigogine and his coworkers. These theories consider the rates of heat production by living beings. However, in this case, the heat effects characterize the intensity of biochemical processes and are only indirectly related to the alteration (aging) of the proper structure of the biological system. One should also bear in mind that changes in the entropy of an open system are, of course, related to not only the heat effects of the processes, but also to exchange of matter and energy with the environment, which makes it difficult to calculate the changes in thermodynamic functions of the systems (Denbigh, 1989).

Here, I would like to consider only the thermodynamic (thermostatic) theory of aging. This theory is based on hierarchic thermodynamics, or macrothermodynamics, which studies quasiclosed systems at certain times. The foundations of the theory of aging have been briefly described (Gladyshev, 1987, 1995, 1996a*, 1997, 1998b). The theory in question, like all physical theories, has limitations. The approximate character of the theory is due to, above all, difficulties in revealing arbitrary direction processes in quasiclosed systems when the thermodynamic stabilities of systems with variable compositions are compared. These difficulties are due to the impossibility of determining the absolute values of some thermodynamic functions. Note, however, that such limitations are imposed on physico-chemical theories of solution and other binary and polycomponent systems, where thermodynamic functions of variable compositions are compared. At the same time, the thermodynamic correlations found confirm that quantitative comparisons of the supramolecular stabilities of biological systems of different compositions may be done in order to reveal the thermodynamic direction of evolutionary (ontogenetic and phylogenetic) processes. It appears that variations in the supramolecular and chemical composition of biosystems during ontogenesis (as well as during phylogeny) are accompanied by averaging and relatively small gradual changes of the standard reference level. In the case of supramolecular systems, the pattern of correlations of the type (where , is the change of the Gibbs function—Gibbs free energy of supramolecular structure formation, is the temperature of melting) is the main criterion of the degree approximation of this model (Gladyshev, 1987, 1995, 1996a, 1996b, 1997,1998a, 1998b).

The above-mentioned gradual change of the reference level appears to be related to a small and gradual change in the ratios between the concentrations of chemical elements in organic (and inorganic) substances (OS), with which the biological tissues are enriched during aging. In other words, a change in or another component as a function of the tissue composition during aging can be satisfactorily approximated in terms of a two-component diagram of state H2O-OS. The overall OS composition is represented by a formula of type CxOyHzNw, and the ratios between x, y, z, and w may be considered, to a first approximation, to be invariable. This assumption means that during ontogenesis the "element nature" of OS essentially does not vary, while the ratio (H2O/(OS) alone undergoes changes.

Let us now consider important facts that should be explained by any general theory of aging.
Fig. 1. Changes in the water and fat content in a developing human embryo (Widdowson, 1967)

1, water in fat-free tissue; 2, water in tissue; 3, fat in tissue; mfat, % and , % amount of fat and water in weight %; M, mass of fetus.


It is necessary to understand the alteration of the composition of living organisms during aging in terms of supramolecular thermodynamics (this term was introduced by the author by analogy with the term "supramolecular chemistry"). Figure 1 shows the changes in the water and fat content of a developing human embryo (Widdowson, 1967).
Fig. 2. Scheme of changes in specific chemical energy capacity of the biological mass (biological tissue) A or and thermodynamic stability of its supramolecular structures during ontogeny of living beings B .
These and similar facts can easily be interpreted from the position of thermodynamics (Gladyshev, 1978, 1997) if we take into account the scheme presented in Fig. 2, where the arrows at axes A and B indicate an increase in energy capacity and supramolecular stability. Growth of means an increase in the chemical energy capacity of the system; shift of to the negative region means an increase in the supramolecular stability of the system. The value A corresponds to the change upon formation of a chemical substance of the system from elements or simple substances (chemical or molecular component). The value B corresponds to the change upon formation of the supramolecular structure of the system during self-assembly (supramolecular component). Scales A and B are different (, is much greater than ). The time axis set by the second law of thermodynamics is scaleless.

Jagged lines plotted onto the curves emphasize the fact that fluctuation of environmental parameters (temperature, pressure, diet, physical fields, time of day, season, etc.) change the levels and . Organisms adapt to these fluctuations only within the limits of the adaptive zone (range of tolerance).

The scheme presented in Fig. 2 corresponds fully to the experimental data obtained from study of embryos (see, for example, Fig. 1) and the tissues of adult plants and animals (for example, Flandin et al., 1984; Gladyshev, 1997; Lepock, 1998).

It follows from the scheme that a trend of the specific supramolecular component of the Gibbs function of biomass (for example, biological tissue) to a minimum is the driving force of ontogeny (evolutionary development of an organism):

,

where V is the system volume; m is the mass of isolated microvolumes; x, y, and z are coordinates; the symbol "-" means that the value of is specific; and the symbol "~" underlines the heterogenous character of the system (Gladyshev, 1997).

Fig. 3. Relationship between characteristic size (l) of structures of various hierarchies and their life span (t) in the biomass. The relationship is plotted in logarithmic scales. The scheme is based on the data for Homo sapiens. The following series is true: , where t is the mean life span of "free" molecules-methabolites, supramolecular structures, organelles, cells in the tissue, as well as organisms, populations, and communities (Gladyshev, 1992).

An increase in the biomass energy capacity (upper part of Fig. 2), i.e., its chemical component or (as well as or changes in the specific enthalpy of the chemical component), during ontogeny is a secondary effect. It is advantageous for the thermodynamics of molecular interactions (or supramolecular thermodynamics), in accordance with the second law of thermodynamics, to preferentially accumulate high energy capacity chemical substances (chemical component ) in a biological system, which force water out of the system.

The scheme shown in Fig. 2 agrees quite well with our calculations (see Gladyshev, 1997). Note that the apparatus of hierarchic thermodynamics is very safe, as it is based on the Gibbs thermodynamic theory. Subdivision of thermodynamic functions into individual components in accordance with the hierarchy of actual structures is possible due to the existence of the unidirectional series of life (or relaxation) times of structures with different hierarchies. Figure 3 reflects this objective pattern, which appears to be a general law of nature (Gladyshev, 1997).

Let us examine the lower part of Fig. 3 and consider the possibility of prolonging life (Gladyshev, 1978, 1995, 1997; Gladyshev and Komarov, 1996).

When studying aging (ontogeny of the supramolecular structure of a biological tissue, organ, or any biological system), it is advisable to investigate the influence of physicochemical factors, such as temperature, pressure, caloric value and type of food, effects of synthetic chemical drugs and natural physiologically active compounds, and effects of ionizing irradiation and physical fields. If aging (ontogeny) proceeds against a background of constant physicochemical factors (they should be considered as parameters of a thermostat—habitat), the ontogeny of a biological system is completed at a definite value of or, which in some cases is close to its minimum.
Fig. 4. Schematic diagram of changes in specific Gibbs function of formation of aggregated phase of the supramolecular structures in a biological tissue of individual organ of the jth organism during ontogeny.
Let us consider the scheme presented in Fig. 4, where curve 1 corresponds to a studied organism j existing under set (standard) life conditions of the population (humans). The course of the curve is determined by the genetic characteristics of the organism j (genotype) and by set environmental conditions (averaged parameters of the thermostat). Curves 1+ and 1- correspond to an individual j existing under the most extreme conditions possible. The area between curves 1+ and 1- corresponds to the adaptive zone of alteration of related to oscillations of the environmental parameters. Rejuvenation or accelerated aging of a biological object, e.g., biological tissue or organism as a whole, is possible within the limits of this zone.

The upper dotted line (Conception) corresponds to the conception of individual (genotype) j, the value of is genetically determined and corresponds to the habitat of the population.

The middle dotted line (Birth) refers to the birth of animal (human) j.

The lower dotted line (Death) corresponds to the death of organism j; the time of death varies in the adaptive zone and is determined by changes in the environmental conditions.

The value of is an increase in the specific Gibbs function of formation of the supramolecular structures of organism j during ontogeny (as a result of aging) from conception to the death of the organism. For example, for aging of the animal tissue collagen, . The value of characterizes the adaptive zone width at a moment t of the life of the organism.

The values of of biological tissues of a specific individual may differ from the mean values characterizing an average individual occurring under average standard conditions; these differences estimated by the value of may have different signs. They are a quantitative characteristic of the degree of aging of organism j at the corresponding moment t of ontogeny.

Darkened areas in Fig. 4 surrounding the dotted straight lines "Conception," "Birth," and "Death" represent the zones of oscillations of the values of, Conception, , Birth, and , Death. A thin, jagged line plotted on curve 1 emphasizes the fact that oscillation of the environmental parameters (temperature, pressure, diet, physical fields, time of day, season, etc.) change the level of . The organism is adapted to these oscillations only within the limits of the adaptive zone.

The patterns of changes in presented in Fig. 4 agrees with theoretical calculations based on the available data concerning the chemical composition of tissue during ontogeny and numerous experimental data obtained by the DSC method (Flandin et al., 1984; Lepock, 1998).

The mean life span of the organism is species-specific and is related to certain averaged environmental conditions. Therefore, the life span is strictly programmed for the habitats of a given species. However, a change of habitat (which, in terms of thermodynamics, means transition to a new thermostat), as in the case of neoteny, malignant tumor growth, or artificial selection during phytogeny, results in a trend of the system to a new value of (2) which may be higher or lower than (1). If the environmental conditions change at a certain moment of life (ontogeny) so that , it is quite likely that the life span will increase. Oscillations of the environmental parameters (Fig. 4) within certain limits (adaptive zone) correspond to rejuvenation or aging of the organism. In terms of thermodynamics, transition from curve 1- to curve 1+ means rejuvenation and transition from curve 1+ lo curve 1-, aging.

Thus, rejuvenation of an organism (organ, functional system, or any zone of biological tissue) is possible (against a background of constant genetic characteristics of this organism) due to changes in the environment conditions (parameters) alone. Moreover, oscillations of environmental parameters (changes in atmosphere or in physical field intensity, etc.) cause oscillations of (or ). These oscillations rejuvenate or age biological tissues of an organism (by changing their morphological structure) within the limits of the adaptive zone (adaptive possibilities) and are an expression of the thermodynamic force of the environment in ontogeny.

Consider, for example, changes in the regime of feeding due to an increased amount of unsaturated fatty acids. Lipid-containing supramolecular structures (tissues) may be rejuvenated. The Gibbs function of formation of these structures () will become less negative (transition from 1- to 1+). This consequence of the thermodynamic theory of aging (Gladyshev, 1997) agrees with the clinical practice of treatment of patients with atherosclerosis by the well-known drugs of the Linaetholum type produced from linseed oil. The drug contains a mixture of ethyl esters of oleic, linoleic, and linolenic acids. These fatty acids have a low melting temperature and positive at 25°C (Gladyshev, 1997). Substitution of high-melting fatty acids and fats for low-melting ones rejuvenates biological tissues. All this takes place in accordance with thermodynamic laws. Other similar examples of rejuvenation of fatty tissues, collagen, and other biological tissues are known. The available facts (Blandamer et al., 1996; Blokzijl, Engberts, 1993; Engberts, Hoekstra, 1995; Flandin et al., 1984; Jones, 1979; Lepock et al., 1995) give confidence that nascent gerontological thermodynamics will make it possible to develop new methods and produce new drugs that would slow the aging of humans and other living beings.

The following application of the thermodynamic theory of evolution of living beings related to the problems of gerontology, dietetics, sports medicine, and other medical-biological disciplines may be formulated as a principle (Gladyshev, 1997a, 1997b). Diets including thermodynamically evolutionarily young products of animal and plant origin enhance long life and improve the quality of human life. The degree of evolutionary youth of a natural food product is determined by its chemical composition and supramolecular structure. These depend, in turn, on the ontogenetic and phylogenetic age of the product and on the habitat of the source organism of this product. The specific Gibbs function of formation of the supramolecular structure of the product is an important quantitative characteristic of the gerontological usefulness of a natural food product.

For example, if a patient feeds on the biomass of ancient, evolutionarily primitive plants and animals, such as algae, molluscs, chondrostean fish, amphibians, and many others, particularly on young individuals, he or she enriches biological tissues to a maximum possible degree with a young chemical substance, building material corresponding to the chemical composition of a young organism. In addition, the habitat of the organism whose biomass is used for food preparation plays an important role in long life. In terms of our theory, well-known facts of long life due to low-calorie diets or application of medicinal drugs that slow food assimilation can be readily explained (Advances ..., 1996; Sohal and Weindruch, 1996; Klatz and Goldman, 1996; The Science ..., 1996; The Yearbook ..., 1997; Gladyshev, 1997a). It is also easy to understand the causes of the positive effect of sea food and high mountain conditions on the health and life span of humans.

The effects of some hormones and other physiological important components on aging also become clear. These substances seem to liquefy the structures of corresponding biological tissues by increasing the levels of their .

Let us consider an application of this principle to diets that decrease the risk of cancer diseases and enhancing cancer treatment.

As concerns chemical composition, the development of a malignant tumor is accompanied by its pathogenic rejuvenation: the tissue is enriched with water, the concentration of lipids sharply decreases, and the concentration of proteins noticeably falls. Hence, it follows that an artificial increase of lipid content in the tumor should slow its pathogenic rejuvenation and, in the case of cancer prophylaxis, decrease its risk.

Apparently, this strategy of controlling and preventing cancer is the most effective from the viewpoint of dietetics and thermodynamics. Another strategy related to a sharp artificial increase of water content in the tissue, such as occurs during starvation, should not be successful, although the Le Chatelier-Brown principle (Gladyshev, 1997) would seem to predict development of a response consisting of stimulation of the organic matter (lipids, proteins, etc.) synthesis. Appearance and growth of a malignant tumor are related, above all, to mutational gene transformation. The response in this case is complicated due to kinetic factors, since the directed arbitrary transformation of the genes or gene blocking requires a long time. This comment reminds us that the most effective methods of cancer treatment may be related to intervention at the genic level.

From the above information, it is obvious that anticancer diets should contain above all an increased amount of unsaturated fats and sufficient amount of plant proteins and vitamins providing for necessary life and protective functions of the organism. These diets should have a distinct general anti-aging orientation in order to exclude negative gerontological effects, especially in old patients. Note that this may also be applied to diets recommended for prophylaxis of cardiovascular diseases, Aizheimer disease, and some other diseases.

Prophylactic and therapeutic diets should be distinguished. Prophylactic diets should above all be recommended to people with a genetic predisposition to the corresponding diseases.

Considering our thermodynamic principle and known experimental data, low-calory diets can be used if the following recommendations are observed.

Diets directed at decreasing risk of cancer. Sugar and great amounts of milk are not recommended. Meat is limited in the diet. Unsaturated fats of plant oils and fish products account for 35-40% calories of the diet. Oils and fish fat with a low melting temperature are preferred. The oils obtained from plants growing in cold climatic zones have a high gerontological value, such as perillic, lallemantic, flax, mulberry, sunflower, and maize oils.

The diet should include fish, preferably cold water fish, such as tuna, herring, cod trout, salmon, etc.

The diet should also include an increased amount of green vegetables and a certain amount of beans (soya, kidney-bean, pea, etc.).

In case of genetic predisposition to cancer, it is important to use 10-fold doses (as compared to the officially recommended doses) of vitamins, C, E, PP (nicyan and nicotinamide), vitamins of group B, vitamin A, zinc and selenium. All other vitamins and mineral substances are used in this case as recommended. These doses are quite accessible as shown by L.Pauling and other researchers (Klatz and Goldman, 1996). It is desirable that the drinking water does not contain an increased amount of iron.

Diets recommended for cancer therapy. All recommendations in the case of prophylaxis of cancer diseases apply. But sugar and milk are fully excluded from the diet, while the doses of some vitamins and mineral substances may be markedly increased.

Thus, the following amounts of vitamins and mineral substances could be recommended on the basis of the available studies (Pauling, 1986; Eades, 1994; Klatz and Goldman, 1996):

Vitamin C 10 g/day
Nicotinamide (vitamin PP) 2 g/day
Complex of group B vitamins 0.1 g/day
Vitamin E 800 IU/day
Vitamin A 30000 IU/day
Selenium 500 mcg /day
Zinc 40 mg/day
Magnesium 0.4 g/day

All other vitamins and mineral substances are applied at doses corresponding to the official recommendations.

Note that the use of exceedingly high concentrations of some vitamins and mineral admixtures is questionable and is criticized, for example, by the Food and Drug Administration of the United States.

One possible mechanism underlying the positive effect of unsaturated (and saturated) fats in cancer treatment consists (from the viewpoint of supramolecular thermodynamics) in that the cell membranes are enriched with lipid components, which enhance cell interactions. This should, in turn, prevent metastasis. Note that many anticancer drugs and vitamins are mostly hydrophobic or contain groups with pronounced hydrophobic properties. This allows us to understand the reported positive effect of high doses of some vitamins in cancer treatment (Pauling, 1986; Eades, 1994).

Note that the recent achievements of the anti-aging medicine agree quite well with the general principles of the thermodynamics of aging and allow additional components, such as coenzyme Q-10, seeds and biomass of Ginko biloba, blue-green algae, chlorella, melatonin, grain thyroid hormone, dehydroepiandrosterone, imizinum, - deprenyl or eldepryl, aspirin, and elevated concentrations of chromium compounds to be introduced into general anti-aging diets (Klatz and Goldman, 1996, p. 317).

The thermodynamic theory of aging developed by the author implies that one task of the food industry is to produce food additives, such as vitamin complexes, which contain all physiologically important ingredients of living tissues. In principle, these should be given in doses such that the concentrations in the tissues of patients taking the supplements are as close as possible to those in young tissues. Production of such drugs would make it possible to rejuvenate not only individual tissues but also the organism as a whole. However, this task is difficult, since new technologies of introduction of the drugs should be developed that would exclude (or reduce to a minimum) negative side effects. For example, introduction of hormones may lead to medicamentous dependence, since synthesis of these hormones would be inhibited according to the Le Chatelier-Brown principle.

The diets should be corrected in the case of accompanying pathologies.

Our recommendations are based on the scheme in Fig. 4 and numerous experimental data (Widdowson, 1967; Nutrition ..., 1989; Lepock et al., 1993, 1995; Mazariegos et al., 1994; Goodnight, 1996; Gladyshev, 1997), as well as on estimates of the stability of supramolecular structures of biological tissues and food products, made by Gibbs-Helmholtz approximated equation:

,

where is the specific enthalpy (change of specific enthalpy) of melting-denaturation , is the mean temperature of melting of the i-th structure, and is standard temperature. The data obtained agree quite well with the experience of medicine and clinical and sports medicine (Advances ..., 1996; Klatz and Goldman, 1996; The Science ..., 1996; The Yearbook ..., 1997).

Note that, when necessary, the values of may he estimated more precisely by using the equation

,

where , is the change of heat capacity of the corresponding supramolecular structures during phase transition (Gladyshev, 1997).

New recommendations presented here make the known recommendations more precise and underscore the expediency of using food products obtained from plants and poikilothermic animals occurring under cold climatic conditions and animals and plants from cold rivers, lakes, and seas. From this viewpoint, food from cold climatic regions, seas, and high mountains are symbols of health and youth. The general quantitative conclusion of the thermodynamics of aging is that food substances and products with low-melting supramolecular structures should show a distinct positive gerontological and sanitary effect on the human organism. On the whole, the optimal diet should positively affect the patient but should not replace the treatment recommended according to the medical indices.

Possible testing of the gerontological effects of medicinal drugs on aging of human biological tissues is another consequence of the thermodynamics of aging. In other words, an additional method of estimating the quality of drugs is now available. As was already noted, many medicinal drugs, including vitamins, trace elements, hormone simulators, and other physiologically active substances, provide for maintenance of the physiologically optimal stability of supramolecular structures of biological tissues. This optimal stability, as estimated according to the Gibbs function of formation of a supramolecular structure, enhances the normal metabolism, slows aging, and improves the quality of life. Corresponding new tests would make it possible to look for the most promising drugs from the viewpoint of structural thermodynamics and to recommend dosages. A preliminary estimate of the gerontological quality of a drug (screening) can be performed based on the available data concerning the chemical structure of the drug and information about the composition and organization of supramolecular structures of the biological tissues where the drug should be localized (lipid structures, for example, membranes, plasma, collagen tissue, etc.). Simple physicochemical tests, such as solubility of the drugs in standard systems, may also be used.

Now we shall consider some facts that have been recently understood within the framework of the thermodynamic theory of ontogenetic and phylogenetic aging.

ON THE PRINCIPLE OF STABILITY OF SUPRAMOLECULAR STRUCTURES OF A BIOMASS
Every structural hierarchy of the biological world represents a community of similar particles. In the hierarchy of small molecules, molecules themselves are similar particles; in the cellular hierarchy; cells are similar particles, etc. In each hierarchy, the unitary particles are kinetically independent and their concentration determines the colligative properties of the system of a given hierarchy.

In some cases, identification of systems of individual hierarchies presents no difficulties (Cantor and Schimmel, 1980; Tanford, 1994; Gladyshev, 1997). This is true, for example, for simple homogeneous ideal chemical systems-solutions. Difficulties may arise when complex heterogenous systems are divided into hierarchies. Thus, in studying a tissue of an organism, it is difficult to estimate the size of supramolecular formations, which fulfill the role of kinetically independent fragments-structures. For example, it is assumed that a kinetically independent fragment of nucleic acids in a solution consists of several tens of nucleotides (Cantor and Schimmel, 1980). From the practical viewpoint, the kinetically independent fragment may be defined as a supramolecular structure that melts in a narrow range of temperatures.

The living tissue is a supramolecular (im) hierarchic structure, which appears as a result of weakly non-equilibrium phase transitions. However, a series of hierarchic sublevels may be identified inside this structure: substructures (fragments, blocks). When the evolution (aging of the organism or population) of such hierarchic substructures is studied as kinetically independent formations involved in phase transitions, comparatively small macrovolumes can be isolated, which contain fragments of macromolecules and low molecular weight substances.

Let us consider two cases.

(1) If the above-mentioned supramolecular structures of macrovolumes are not spatially isolated and are formed at similar rates, i.e., in the same time scale, their selection in ontogeny and phylogeny is determined by the change of the complete Gibbs function of their formation. The value of consists of many components corresponding to different types of interaction (see, for example, Cantor and Schimmel, 1980). Furthermore, characterizing the degree of completion (extent) of evolution (ontogeny, phylogeny) of the hierarchic sublevel in question tends to a more negative value. Thus, in this case, while individual i-th components of may exceed zero.

(2) If the times of formation of particles of the hierarchic sublevels markedly differ and the higher sublevel stabilizes the lower one, the structures of these sublevels may be considered as independent hierarchic structures j, j - 1, etc. In this situation, alteration of the Gibbs function of formation of the higher level j is the driving force of evolution; i.e., and . However, the value of characterizing selection of structures at the lower level may exceed zero. Here, just as in the previous case (1), we observe an analogy with an increase of against the background of a general decrease of in the simplified model presented in Fig. 2. Note that these postulates should be considered as specific for the model in question (Figs. 2 and 4).

Thus, the principle of stabilization of the chemical substance formulated by the author (Gladyshev, 1997) appears to be applicable to both considered cases. The principle is as follows: when forming the most stable structures of the higher hierarchic level (j), nature predominantly uses the least stable structures of the lower hierarchic level (j-1).

There are reliable experimental data confirming the applicability of this principle to RNA evolution. For example, during evolutionary optimization of RNA structure (Schuster, 1993), selection of AU pairs (which are the least advantageous from the viewpoint of thermodynamics of secondary structure formation) is determined by the thermodynamic stability of higher supramolecular structures.

Similar results were also presented by Mashkova et al. (1990), who showed that evolution of the 5S rRNA secondary structure of higher plants was accompanied by an increase of component of the secondary structure, which became less negative. Undoubtedly, the most stable ribonucleic complexes, higher structures that are predominantly formed from the least stable fragments of the RNA secondary structure, are selected during evolution. Thus, selection of these fragments of the secondary structure is preferable.

Both considered facts concerning RNA evolution correspond to the principle of stability of chemical substance. This gives the impression that this principle is applicable to various hierarchic levels of matter during evolution of living systems. It may well reflect an important property of living matter, i.e., a trend to formation of higher, relatively more stable structures through involvement of lower, relatively less stable (energy-consuming) structures in spontaneous formation of the aggregated substance.

Let us stress once more that the principle of stability of chemical substances is a thermodynamic principle. It correlates with the principle of structural stabilization (Gladyshev, 1997) and states that the trend of a biological system in evolution (ontogeny and phytogeny) to the appearance of relatively more stable structures of higher hierarchies leads to the selection of relatively less stable structures of lower hierarchies. This evolutionary trend of biological systems seems to rejuvenate the lower hierarchic structures (preserves the optimal stability of these structures) and causes a practically unlimited development of the biological world.

It is also important to note that the thermodynamics of the aging of biological systems should be studied in terms of specific (partial) equilibrium. It was already noted that within the supramolecular (im) hierarchy, it is often advizable to isolate several spatial and/or temporal subhierarchies. Identification of temporal subhiearchies is based on the difference in the times of relaxation of establishment of specific phase intermolecular (im)-equilibria in the various subsystems in question. Thus, the general (complete) im equilibrium between relatively large supramolecular structures, for example, molecules of complex proteins or membrane fragments, is rapidly established only in small local volumes. Specific im-equilibria involving low molecular weight components may be established relatively rapidly in the entire organism. These equilibria are exemplified by specific im-equilibria involving water molecules, other low molecular weight substances, and ions. Electrochemical equilibria may be established practically instantaneously between biological structures located at great distances from each other in an organism.

Some researchers (Lepock et al., 1995; Engberts and Hoekstra, 1995; Lipatov, 1997; Gladyshev, 1998; Lepock, 1998) do not question the general postulates of this thermodynamic theory of aging (Gladyshev, 1978, 1995, 1996, 1997), which has been experimentally confirmed. However, many details of the thermodynamic direction of aging remain unknown. Additional experiments would not only make the theoretical model more precise, but might also make it possible to obtain new evidence supporting the applicability of the second law, in its classic formulation, to the origin and development of life on Earth or in the other areas of the solar system and universe.

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