ISSN 2079 0570, Advances in Gerontology, 2011, Vol. 1, No. 2, pp. 135142. Pleiades Publishing, Ltd., 2011.

. Original Russian Text A. G. Boiko, Yu. A. Labas, A. V. Gordeeva, 2010, published in Uspekhi Gerontologii, 2010, Vol. 23, No. 1, pp. 2129.

An Outline of the Phylogenetic History of Metazoan Aging (Creation of the General Theory of Metazoan Aging)
A. G. Boiko, Yu. A. Labas, and A. V. Gordeeva
Mechnikov Odessa National University, ul. Dvoryanskaya 2, Odessa, 65026 Ukraine e mail: boyko l@rambler.ru
Received July 2, 2009

AbstractThe phenomenon of aging in Metazoa has evolved from initially potentially immortal variants to forms ever more prone to aging. Potential immortality is an ancestral feature, which has been gradually lost during evolution, while aging and death by senescence are nonessential, yet very desirable, properties for the existence of the Metazoa with sexual reproduction, being a prerequisite for evolutionary progress, since, dur ing the stage of species establishment, this enhances the speciation processes accelerating the radiation of phylogenetic groups and gives remote evolutionary advantagesacceleration of both the evolution and the rate of replacement of one species by others. The main principle in the evolution of the aging phenomenon is substitution of external death factors of nonaging metazoans by internal death factors programmed in the genome. The aging mechanisms reduce to limitation of the repair and regeneration capacities of the adult phenotype and/or to complete or partial extermination of the stem cell pool. Aging is an integral process that cannot be reduced to one of the known cellular processes, which, in turn, cannot be an initial trigger of aging programmed in the genome in an implicit form (as there is no aging program per se): if disabling of the repair mechanism is genetically programmed at a certain stage of ontogenesis, this is actually the programming of the aging phenomenon. Mainly a complete or partial postmitotic design of an organism is programmed, and this, in turn, is a factor providing for harmfulness of the cellular mechanisms decreasing in an age depen dent manner the physiological potential of an organism, thereby increasing the probability of Metazoa spe cies dying. In general, the described data suggest that development of a general theory of aging in Metazoa does not require considerable addition to the database of biological science; however, a new understanding of the known facts is necessary, as this determines the initial cognitive position. Keywords: Metazoa, aging, evolution, cellular mechanisms, general theory of metazoan aging. DOI: 10.1134/S2079057011020044

CAUSE AND ORIGIN OF THE FIRST AGING MECHANISMS IN METAZOA It is assumed that the first metazoan organisms appeared on Earth no earlier than 2.1 billion years ago [21]more precisely, between 1.8 and 1.5 billion years ago [20]. The first Metazoa were one layered spherical organisms slowly swimming in water, the organization of which is recapitulated by the blastula like larvae of the modern metazoans [18] According to Ivanov [8], the transition of several cnidarians to a sessile life gave rise to primitive single polyps, which, in turn, gave rise to freely swimming medusas and sessile coral polyps. A sessile life, which hinders dis persal of the products of asexual reproduction, had led to development of a colonial life style. The primary movement mode with the help of flagella is retained only in metazoan larvae, which first recapitulate the organization of a Protomonadida colony and, then, phagocytella; however, they acquired an important dispersal value [11]. In general, some authors believe that the primary metazoans were sessile and others that they were free moving, since the available data are

too few for any strict conclusions except for the rather well studied Ediacaran (Vendian) fauna, preceding the Cambrian Explosion, which was mainly repre sented by modular segmented forms [39]. This is why Dewel [32, 33] believes that the Bilateria individual is the result of integration of a cnidarian colony into an individual of higher order, namely, an integral organ ism, which agrees with the presence of numerous colonial forms (Charniodiscus, Thaumaptilon, etc.) in the Precambrian fauna. Presumably, the evolutionary need for primary aging mechanisms emerged in the period of evolution that preceded the integration of colonies into a higher order individual. Even modern modular forms fre quently display aging of modules. Older modules [30] age and die; however, the growth and maturation of younger modules accompany their aging and death. The aging of one module does not obligatorily influ ence the physiology of any other. Such asynchronous aging within a particular genome takes place because the modules of a modular organism are to a certain degree physiologically independent of one another

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[30, 43]. Several colonial ascidians display mass pro grammed death of the zooids forming a colony, i.e., the pool of zooids is changed in a cyclic manner. The cycle reaches its highest point when all zooids of a col ony simultaneously die and are replaced by new ones [49, 55]. According to Makrushin [15, 17], the primary aging mechanism originated at the colonialsessile stage in the evolution of Metazoa. The modular organ ism is a donoracceptor system. Destruction of important organs in the sessile colonial metazoan spe cies is a component of normal ontogenesis, which accompanies iteroparous and semelparous asexual reproduction [16]. An old module may die off, giving its resources to a new one. The nutrients from one module are conveyed to others, determining the local aging of an unnecessary module when a colony needs to change its shape due to changes in its envi ronment. This process is accompanied by involution of parenchymal cells and, eventually, death of the module. The colony that developed from a zygote rep resents an individual possessing a unique genotype. Therefore, death of modules does not accelerate their evolution, since this does not lead to the death of an individual but rather rejuvenates it. Each module forms several daughter modules before it dies. Mak rushin [13], referring to several authors [25, 41, 52 54, 56], concludes that, due to young modules replac ing old ones, an individual of both the first metazoans on the Earth and many currently existing modular species was potentially immortal. THE EVOLUTIONARY STAGE OF TRANSITION FROM MODULAR TO UNITARY METAZAOAN ORGANIZATION. THE ORIGIN OF AGING MECHANISMS IN AN INTEGRATED ORGANISM According to Makrushin [1317], the sessile life style of the first metazoans on Earth limited their capacities for using environmental resources. There fore, selection favored origination of properties allow ing for active movement, which was accompanied by an increase in the integrity of the individual. The destructive processes taking place during aging of uni tary species are the derivatives of senile involution of the unnecessary modules in modular species. They appear when the ability to asexually reproduce is lost due to increase in the integrity of the organism, onto genesis becomes irreversible, and organisms become unitary. Then Makrushin speculates that the evolutionarily unitary organism is a module of the colony that lost its ability to asexually reproduce, in which the proliferat ing connective tissue, replacing the cells of vitally important organs, is a homolog of the blastogenic zone. During aging, the connective tissue acts on the parenchymal tissues via establishing donoracceptor relations. The parenchymal tissues become donors,

and the connective tissue becomes the acceptor. How ever, the hypothesis that the unitary vertebrates are an evolutionary derivative of a neonatal ascidian larva, i.e., an independent module of these animals, came to naught. It has been demonstrated that Urochordata, including Ascidiae, are just a sister group of Vertebrata [58] and cannot be their ancestor. As for the colonial nature of Urochordata, it is likely to be secondary. The idea that unitary animals are nothing but mod ular animals composed of a strictly genetically deter mined number of specialized modules and segments, somites, etc., that have lost their apical points is more fruitful. Indeed, the majority of currently existing uni tary animals are metameric (Annelida and Arthro poda) or have a metameric stage in their embryogene sis (Vertebrata). Therefore, it cannot be excluded that the design of Bilateria is a colony with its specialized modules integrated into a higher order individual, a unitary organism. As we see it, a metamer, somite, or segment is a specialized module. Presumably, the spe cialization and integration of zooids of a colony into a higher order individualan integral organism resem bling metameric Annelida and Deuterostomiatook place in the Prevendian period, since the majority of Vendian metazoans were already segmented. None theless, residual modularity is observed in several modern polychaetes, for example, Pygospio elegans acquires additional segments until the end of its life, whereas other polychaetes, for example, Nereimyra punctata, have a constant number of segments. Even the unitary Mammalia display the same pattern, some of them being modular organisms at the early stages of embryogenesis [10]. An illustrative example is monozygotic twins, which are the result of asexual reproduction of blastula. In fact, these are two mod ules that lose their modular properties during embryo genesis. We believe that the modular properties of motile colonial modular forms degenerated during the evolu tionary transition from modular to unitary organisms. When speaking of degeneration of modular properties, we mean the loss of apical growth point at a certain stage of ontogenesis with stabilization of morphologi cal design of the organism, including its geometrical shape. Our opinion1 in many respects coincides with that of Korotkova [12] and Marfenin [19], as well as with the hypotheses of the primary colonial pattern [32, 33] and origin of Vertebrata and their segmenta tion [5]. In discussing the evolutionary origin of the aging phenomenon in a unitary organism, note that age related replacement of parenchymal cells by the con nective tissue takes place in Mammalia. However, the nature of this phenomenon is associated with a mech anism (see below) differing from that described in the
1 The

history of the hypothesis that a unitary structure of animals is a result of specialization of the modules of their colonial ancestors is described by Ivanova Kazas [9]. Vol. 1 No. 2 2011

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hypothesis by Makrushin [14, 15] and cannot be an argument favoring it. Nonetheless, aging and age related changes take place in the lower Bilateria forms, which it is logical to explain by donoracceptor inter actions between the degenerate modules, which are observed in the modern colonial modular species. However, the reversibility of the destructive processes in colonial species has been lost during evolution and their action in unitary organisms changed: the involu tion of parenchymal cells in the functioning modules commenced, causing death of senescence of the inte gral organism. EVOLUTIONARY ORIGIN OF SPECIALIZED PROGRAMMED AGE DEPENDENT SELF DESTRUCTION MECHANISMS (ADSDMS) IN SEVERAL BILATERIAN PHYLOGENETIC BRANCHES Presumably, forms capable of evolving faster won out in the evolution of unitary species. The only way of accelerating evolution is limitation of lifespan, which is the factor that determines the speciation rate during reproductive isolation. Analysis of the evolutionary design of the modern forms suggests that the transition to a unitary organization in several metazoan groups determined the emergence of programmed aging: phylogenetic branches with ADSDMs in their evolu tionary design (for example, Nematoda, Insecta, and Mammalia) are currently dominant; presumably, this increased their evolutionary rate. Two main schemes of ADSDMs are found in Metazoa. Their origin is a manifestation of the general evolutionary principle replacement of external death factors in nonaging metazoans by internal death factors. Here we mean that, in the primitive forms, for example, the hydra, the death of the stem cell (SC) pool for some external reason leads to aging and death, whereas in several higher forms, the death of the SC pool (or part of it) is programmed in an age dependent manner and leads to death of the entire organism. The first scheme. On completion of embryogenesis, adult individuals lose SCs, while the somatic cells or the overwhelming majority of them pass into a postmi totic state. The postmitotic cells have limited repair capacities and lifespan (similarly to all the other spe cialized cells of the body, developing from the SCs by asymmetric mitoses). Their lifespan is actually the fac tor that limits the lifespan of the overall organism. It is difficult to estimate how this problem has been evolu tionarily solved from the standpoint of molecular mechanisms; however, several causes of age related impairments in postmitotic cells have been deter mined [31]: nuclear pore complexes (NPCs) are disas sembled during mitoses and reassembled in the newly formed nuclei. However, the fate of NPCs in the post mitotic cells is different: unlike the other nuclear structures, the NPC pool is not refilled during the cell life. More precisely, we mean that the structural nucle
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oporins, such as the Nupl07160 complex, are long living and are preserved in the nuclear membrane to the end of cell life. The absence of expression of this protein class has been demonstrated. Moreover, age related NPC damage has been found that increases nuclear permeability and the release of cytoplasmic proteins into the nucleus. It has been shown that the pool of nucleoporins in old cells is oxidatively dam aged, while the nuclear leakage increases with aging, which, in turn, changes the gene expression profile in the aging cells. In other words, accumulation of damages in the NPCs may be the decisive factor in cell aging. Presumably, the evolutionary origin of such a post mitotic scheme is connected with the solution of another important problem: conflict between the body size and viability, which has developed in several unitary organisms. The body size belongs to funda mental characteristics of any object. For motile meta zoan forms, this parameter is important, since food availability and the amount of it necessary to maintain animal life, locomotion speed, metabolic level, and other characteristics depend on the animal size [23]. Even stabilization of the geometric shape and the number of degenerate modules (segments) does not mean cessation of linear growth in the body size of organism. The simplest evolutionary solution concur rently preventing potential immortality, body growth, and asexual reproduction is elimination of the SCs from the body of adult individuals on completion of embryogenesis. Such an evolutionary design has repeatedly originated among various metazoan phyla, for example, Appendicularia, Nematoda, Rotifera, and Insecta. The reverse of the coin is the loss of regeneration ability, death upon any small physical damage, and accelerated aging. The second scheme is implemented in Mammalia. Nonaging species among the Vertebrata phyla are met in fish, tailed amphibians, turtles, and, possibly, birds. On the other hand, no nonaging species are known among the theriomorphs either from the fossil records or among the modern Mammalia species.2 Aging with extremely similar pathophysiology is observed in all the Mammalia species [48]. These facts suggest that an additionaland the mainreason for aging in Mam malia appeared at the very beginning of their evolution. The aging scheme in Mammalia evolutionarily originated as a result of modernization of one ele ment in the ontogenesis of the vertebrate nervous sys tem: the sites for generation of neuroblasts in adult and embryonic phenotypes and their final localization are separated. In an adult phenotype, neuroblasts migrate from the ventral/subventral regions along the radial glial cells; however, while all vertebrates retain this
2 There is a paper by Buffenstein [28] on the negligible senescence of

the naked mole rat (Heterocephalus glaber); however, the author gives no convincing data on the negligible senescence of the individ uals belonging to this species except for their paradoxical longevity.

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pattern during the entire life, the radial glia in Mam malia soon after birth are transformed into astrocytes and the migratory pathways for neuroblasts disappear. In other words, aging in Mammalia is nothing but a genetic disease with a lethal outcome, the cause of which is the evolutionary acquisition of one trait by the vertebrate theriomorphic lineage, namely, transforma tion of the radial glial cells into radial astrocytes during postnatal development, i.e., the disappearance of embryonic radial pathways for migration of neurons from proliferative zones to the sites of their final local ization in the adult brain, which render the mamma lian brain postmitotic. The disappearance of radial glia induces a cascade of systemic processes, which are nothing more than age dependent mechanisms of self destruction: disappearance of radial glial cells prohibits the replacement of neurons that have exhausted their vital resources, neurons being strictly specialized cells with limited repair capacities and lifespan, which, it cannot be excluded, senesce according to the earlier described scenario [31]. Upon the expiry of a certain time, irreversible pathological processes in neurons (especially in the hormone syn thesizing neurons) lead to a steady and adverse change in the level of homeostasis, damaging the life support ing systems in the Mammalia organism and thereby interrupting the course of its life, while the maximum lifespan is determined by the metabolic rate in the body. These facts are the foundation of the astrocytes hypothesis of mammalian aging [1, 27], which, in turn, explains the processes well described in the ele vation aging theory of Dilman [4, 35, 36] as a result of disappearance of radial glial cells in adult mammals. Dilman believed that while the stability of the internal body medium is an obligatory condition for its exist ence, programmed disturbance of homeostasis is the condition for its development. In other words, there is an age dependent mechanism of postnatal juvenile development of the organism based on the change in sensitivity of the hypothalamus to the regulating sig nals. However, the mechanism during the reproduc tive period enters a pathological phase and its further functioning leads to adverse changes in the homeosta sis. The sensitivity of the hypothalamus to the inhibi tory effect of the factors signaling via a negative feed back on the state of three main homeostatic systems energetic, reproductive, and adaptivedecreases; adverse changes take place with age, as well as the development of characteristic age related diseases; in general, everything reduces to an age related decrease in the ability of the hypothalamus to detect signals from the periphery, which is determined by a decrease in the hormone receptors on the surface of hypotha lamic neurons (according to other data, changes with age [22]). As is known, Frolkis made titanic efforts to refute the ideas of Dilman; however, even if several conclusions of the elevation theory of aging appeared false, this in no way discredits the ontogenetic model of aging proposed by Dilman [3, 34]: (a) fulfillment of

the program of organisms development requires a programmed disturbance of homeostasis; (b) change in the sensitivity threshold of the hypothalamus to reg ulating signals causes the necessary homeostasis dis turbance, which plays the key role in the juvenile development; and (c) preservation of this mechanism after completion of development transforms the devel opmental program into aging mechanism and the main aging linked diseases. If the ontogenetic model of aging more or less cor rectly reflects aging in Mammalia, then it will be maintained and improved. Incorporation of the astro cyte based aging hypothesis [1, 27] into the ontoge netic model of aging in Mammalia will not be the last stage in its improvement. Presumably, the results of the above mentioned studies commenced by the team of Hetzer [31], which has already discovered several basic mechanisms of cell aging in postmitotic tissues, including neurons, will be such a stage. Moreover, these early schemes already require corrections: Finch [40] discovered that the glial cells expanded with age and strangled neurons, thereby increasing the aging process. In Mammalia, this process is induced by the Zuev factor [6, 7]. Injection of the Zuev factor to young animals induced expansion of the glia and accelerated aging. Presumably, production of the Zuev factor is switched on at a certain age related level of homeostasis (age dependent ratio of hormones) and the senile period, the final stage of life, commences. MECHANISMS EVOLUTIONARILY MODULATING THE SPECIES SPECIFIC LIFESPAN OF MAMMALIA AND THEIR CONTRIBUTION TO AGING Obviously, it is impossible to encompass the boundless: it is possible to modulate several parame ters in postmitotic designs, and this can change the species specific lifespan (this is discussed in our next paper). This part of our work describes the coexistence of aging and carcinogenesis phenomena in the mam malian organism. Semelparous asexual reproduction3, according to Makrushin [13, 17], is the evolutionary precursor of carcinogenesis; it commences in modules of colonial forms being induced by adverse environmental fac tors, i.e., this genetic program switches on at the moment when these modules cease maintaining the optimal level of homeostasis. For example, ascidians, before a seasonal deterioration of habitation condi tions, form dormant modules (dormant buds or blas togenic diapausing early embryos, an analog of the cancer tumor in Vertebrata) intended for surviving an unfavorable season. However, during warm winters, such completely formed embryos are subject to invo lution in several ascidians [29, 37]. The involution of a
3 More

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blastogenic embryo during its preparation to diapause is the evolutionary precursor of tumor regression. It is commonly known that an insignificant number of cancer diseases end in spontaneous recovery, i.e., in regression of the tumor. Consequently, there are mechanisms and substances that make the organism cancel the command for cell division in the zones of blastogenesis in lower Metazoa or get rid of tumors in Vertebrata. Presumably, a stable species specific opti mal level of homeostasis is unfavorable for switching on the atavistic mechanisms of somatic embryogene sis. Therefore, it is possible to find many metazoan species with negligible senescence and a similarly neg ligible level of carcinogenesis, since physiological regeneration of all the cell types constituting their body, including hormone synthesizing cells, takes place during their entire life. What is the mammalian organism with a postmi totic brain? With exhaustion of the vital resource of neuroendocrine cells, the level of homeostasis con stantly changes (Dilmans process) and, presumably, the X hour comes at a certain point of life, when changes in the homeostasis commence, triggering the atavistic mechanisms of somatic embryogenesis in stem cells. Presumably, the first Mammalia or their precur sors, at the moment when the postmitotic brain appeared, were small, short living forms. However, starting from the early Jurassic to Eocene, the specific fraction of oxygen in the atmosphere doubled from 10 to 23%. According to Falkowski [38], the saturation of the atmosphere with oxygen gave Mammalia an evolu tionary impetus. Large eutherians appeared with an increase in O2 concentration. According to recent data [47, 51], the dawn of Mammalia began in the early Jurassic, or even in the Triassic, and was accompanied by transition of a considerable part of forms into medium and large size classes. The large body weight of warm blooded animals allows the metabolic load on the organism to be decreased, which in itself should increase the lifespan. Presumably, purely metabolic measures for increas ing the lifespan were insufficient. The increase of the O2 fraction evidently contributed to the reduction of the short lifespan of Mammalia. An increase in the lifespan in the epoch of gigantomania was a vital necessity for Mammalia, since it is impossible to reach the size of an elephant or bear a giant kid in one or two years. However, evolution succeeded and it became impossible to exclude the prohibition on the repair of nervous tissue from the mammalian evolutionary design, thereby canceling the majority of phenomena connected with mammalian aging. The only way to increase lifespan under such circumstances is age related extermination of the stem cells and their clones in an adult phenotype. The evolutionary solution was quite unexpected, namely, a strengthening of the immune system that caused destruction of a considerable part of SCs dur
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ing the postnatal ontogenesis. One must admit that this particular immunological innovation actually fine tuned the life supporting system of Mammalia, so that several species, in particular, humans and bow head whales, do not yield in lifespan to some species of other taxa displaying no aging signs. Nonetheless, there can be absolutely no question of negligible senescence in this case. The described pattern is confirmed by results of several works, namely, (1) SCs are present in all the adult mammalian tissues; however, they are very few and poorly perform their functions, presumably, because they are aging [59]; and (2) cell aging is likely to interfere with the beginning of carcinogenesis [57]. In denying SC aging, we interpret this fact of age related damage of SCs in another way; for exam ple, Mammalia display an age related suppression of the stem function. According to Campisi [24], such age dependent damage of SCs is implemented via an age related increase in the synthesis of p16INK4a pro tein. This conclusion is indirectly confirmed by the experiments of Heber Katz with MRL mice, in which various organs, such as the heart, fingers, tail, and ears, were ablated or traumatized to observe their regeneration. The immune system of MRL mice is damaged (T cells are absent), and they have unlimited regeneration capacities, although they live less than the wild type [50]. Heber Katz believes that regenera tion is characteristic of only those animals that have no T cells, the number of which in the body increases with age. Thus, Mammalia have the necessary genes for tis sue regeneration similar to Amphibia; however, the T cells of the other mouse strains and the wild type (among the remaining Mammalia) interfere with the work of these genes. It has been demonstrated that, with an increase in the number of T lymphocytes in the blood of young MRL mice, they lose the ability to regenerate. On the contrary, blocking of T cells in the blood of adult mice of other strains makes them capa ble of regenerating their tissues [45]. The only organ of MRL mice unable to regenerate is their brain [42], since the prohibition on repair of the nervous tissue is implemented by a mechanism independent of the immune system, namely, elimination of the radial glial cells in the early postnatal period [1, 27]. According to Heber Katz [44], Vertebrata initially had both an immune system and regeneration. How ever, during evolution they became incompatible with one another: the regeneration system is active in Amphibia and inhibited in Mammalia, since the mammalian lifespan is in many respects determined by the balance between the ability of self renovation of SC tissues and the risk of carcinogenesis with an increase in regeneration [24]. Thus, the immune sys tem, protecting the organism from infections and con currently inhibiting the regenerative function, decreases the probability of carcinogenesis, i.e., it simultaneously contributes to both aging and preven tion of carcinogenesis. Presumably, adverse changes in

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homeostasis with age can aggravate the immune inhi bition of the stem function; however, this is a very important phenomenon, since the MRL mice live less than the wild type, although p16INK4a gene knockout, preventing destruction of several types of mouse SCs, increases the rate of cancer [24]. One can object that our ideas do not deserve dis cussion, since thousands of papers describe the muta tions of oncogenes associated with cell transformation and carcinogenesis; the search for particular muta tions is a conventionally used method for diagnosing dysphasia; and so on. Thus, it looks as if the authors reject all this practice by a dash of the pen. However, carcinogenesis, according to Makrushin, is the transi tion of a unitary organism into a modular state, while the tumor is an atavistic growing module preparing to diapause [1317]. Consequently, the genome of can cer cells must not be damaged by mutations and must not differ from the genome of the remaining cells in the body, while carcinogenesis is a mere implementa tion of a genetic program. This assumption was recently confirmed, thereby undeniably verifying the hypothesis of Makrushin: it has been proved that can cer cells under certain conditions can transform into normal cells. Nuclei from melanoma cells were trans ferred into mouse ova, which commenced developing. SCs were extracted from the embryos and placed into mouse blastocysts. Some of these embryos developed into healthy mice. It is important that the SCs from cloned melanoma were incorporated into the majority, if not all, of the tissues of adult mice [46]. If cancer cells can develop into normal healthy cells, this con firms the hypothesis of Makrushin: carcinogenesis is the result of switching on of the genetic program rather than accumulation of mutations. These ideas coincide with the opinion of Golubev and Dilman [2] that pro liferation of cancer cells is their preparation for further differentiation. Presumably, cancer begins when sev eral genes are changed in an epigenetic manner, whereas the DNA sequence is preserved. It cannot be excluded that mutations in oncogenes can trigger the atavistic program of somatic embryogenesis or, in other words, the genetic program of carcinogenesis. However, it seems that they have nothing to do with the performance of the cancer overture. Moreover, it is reasonable to take into account the results obtained by Belogolowy [26] in experiments with frogs. Eggs and tadpoles at different developmental stages were placed into the body cavities of adult frogs. Some of them survived, having attached inside the body to one of the organs. Their tissues fused. The frogs blood entered the tadpoles body, supplying its cells with nutrients and oxygen. The tadpole com menced dedifferentiating: the integuments disap peared, the organs changed, limb buds disappeared, and the cartilage skeleton dissolved; the body lost its shape, transforming into an irregular clot, etc.; the tis sues acquired an embryonic pattern; and their cells acquired an autonomous motility; thus development

was directed toward simplifying the organization. Thus, the embryogenesis in the medium of a highly organized adult organism is pathological and cannot be completed. The eggs placed into the frog separated into individual cells, which migrated within the body attacking its tissues similar to cancer cells. The behav ior of parasitic egg cells and tadpoles resembles that of cancer cells. In a similar manner, an atavistic somatic embryogenesis (cancer) within a highly organized organism ends in its death, which is not surprising in the light of the above described facts. CONCLUSIONS The data reduce to a natural conclusion: the evolu tionary vector of aging phenomenon was directed from initially potentially immortal forms to forms ever more prone to aging. Thus, potential immortality is an ancestral property that has been lost during the evolu tion, whereas aging and death are nonobligatory, yet most desirable, attributes in the existence of Metazoa with sexual reproduction, since aging enhances speci ation during the stage of species establishment, which accelerates radiation of phylogenetic groups, and pro vides remote evolutionary advantagesacceleration of both evolution and the rate of replacement of one species by others, thereby creating conditions for evo lutionary progress. The evolutionary principle of the aging phenomenon is substitution of external death factors in nonaging metazoans with internal death fac tors programmed in the genome. The aging mecha nisms are reduced to limitations of the repair and regeneration capacities of the adult phenotype and/or to complete or partial extermination of the stem cell pool. Aging is an integral process, which cannot be reduced to one of the known cellular processes, which, in turn, cannot be an initial trigger of aging. The data on biology of aging shift the cellular processes under lying various aging hypotheses from the primary causes of aging to secondary, tertiary, and even insig nificant aging factors. The aging process is pro grammed in the genome in an implicit form (as there is no aging program per se): presumably, the first meta zoans had powerful repair systems, which provided for potential immortality. If disabling of the repair mech anism is genetically programmed at a certain stage of ontogenesis, this is actually the programming of the aging phenomenon. Predominantly, the programmed features are a postmitotic design of the body cells, which is the factor providing for harmfulness of the cellular mechanisms, decreasing the physiological potential of the organism in an age dependent manner and thereby increasing the death probability with age (not only in the higher metazoans). Aging is imple mentation of the genetic program frequently con tained in the genome in an implicit form and deter mining the particular age dependent mechanism of self destruction.
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