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Boyko O. G. 2007. Differentiation of radial glia cells into astrocytes
is a possible ageing mechanism in mammals \\ Zhurnal Obshchei Biologii
(Journal of General Biology). V. 68 № 1 P. 35-51
Differentiation of radial glia cells into astrocytes is a possible ageing mechanism in mammals
O. G. Boyko
National Agrarian University
ul. Geroyev oborony 15, Kiev 03041, Ukraine
e-mail:
Several obscure facts of gerontology are briefly reviewed. The attempt is made to shape new notions of the phenomenon based on the astrocyte hypothesis of ageing in mammals. This hypothesis interprets mammal ageing as a genetic disease with fatal outcome. The disease is caused by single character acquired by the theriomorph lineage of the vertebrates in the course of evolution: the transformation of radial glia (RG) cells into star-shaped astrocytes during the postnatal development, i.e. the disappearance of the fetal radial ways of nerve cell migration from proliferative zones to the sites of their ultimate localization in the brain of adult individuals. This process is the cause for the mammal brain being postmitotic. The disappearance of RG cell induces a cascade of system processes termed age-dependent mechanism of self-destruction of mammals (AMSM). The disappearance of RG cell inhibits the replacement of the nerve cells that have exhausted their living resources. Nerve cells are rigidly specialized and have restricted lifetime and ability of reparation. After some period, the level of homeostasis in nerve cells starts changing steadily for the worse due to irreversible pathological changes in the cells (especially in the neurosecretory cells). This brings damage to life-support systems of the mammal organism thus causing its death. The species-specific maximum life span is thus determined by the rate of metabolism in the organism. AMSM probably displays a general evolutionary principle: outer factors causing death (in non-ageing organisms) are replaced by inner factors.
Till now the discussion started still in days of A. Weismann about an acceptability of two concepts of ageing is not stopped: death as result of an accumulation of casual breakages or starting of the program of "suicide". In a number of reviews (Khalyavkin, Yashin, 2003) a conclusion is made that even such standard concepts as free-radical and telomere – telomerase hypotheses are not quite suitable for an explanation of an original cause of ageing. Williams (Williams, 1957) summarized arguments against the idea of programmed death: in the nature practically all animals die at rather young age from the casual reasons. In other words - if there is a mechanism of programmed death it cannot define life-span at overwhelming number of individuals of a population; searches of the mechanism of programmed death were not successful; it is difficult to imagine how such attribute (the program of death) could arise during natural selection.
Therefore today a number of known gerontologists, for example spouse L.А. and N.S. Gavrilov (Gavrilov, Gavrilova, 2002), Weismann’s ideas (Weismann, 1889) that ageing and death, is «something secondary arisen during adaptation» (the theory of programmed death -PDT), call precisely "deceased".
V.P. Skulachev (1999, 2001), trying to update PDT, has offered the phenoptosis, concept. The programmed death of an organism, or phenoptosis, is a self-liquidation of an individual in interests of a population, and also its last boundary of protection against epidemics and monsters with the broken genetic program. In view of these ideas the death from an old age is considered as one of many displays of phenoptosis, caused by starting of the program of self-liquidation at the individuals which have appeared useless or harmful for population.
As if to concrete mechanisms of ageing the analysis of the literature allows to draw a conclusion, that the majority of authors, for example Johnson (Johnson et al., 1999), are sure, that it is possible to reduce a phenomenon of ageing to a small number of cellular and all organism processes, such as programmed cellular death or apoptosis, accumulation of damages by molecules mitochondrial DNA (mtDNA), shortening of telomeres at mitosis, defects of a cellular cycle, etc. V.P. Skulachev allocates a key role during ageing to apoptosis. His arguments seem convincing, however they have not made due impression on other researchers. Objections cause representations about a parity and interdependence of phenoptosis, organoptosis and apoptosis, the chain of events is more exact than the programmed destruction of separate bodies: The programmed destruction of mitochondria or mitoptosis, - apoptosis, - organoptosis - phenoptosis, (Skulachev, 1999) as it is obvious, that relations between these processes is much more complex and are poorly predicted (Vanyushin, 2001; Kaluev, 2003). The impression is created, that the facts mentioned by V.P. Skulachev have individual character, frequently they are discussible enough and can be treated differently depending on belief of the researcher (Kaluev, 2003).
THE REASON OF DISCREPANCY OF KNOWN THEORIES OF AGEING
Discussing this or that theory of ageing, authors, as a rule, miss existence of species of multicellular organisms which actually are not subject to ageing and possess potential immortality with that do not interfere generation of reactive oxygen species, telomeres shortening, apoptosis and other processes with which ageing usually explain. Moreover, these species have long evolutionary history, and their evolutionary progenitors in most cases also were potentially immortal. Ignoring of these fundamental facts of gerontology, probably, has very simple reason - researchers cannot explain them.
Unfortunately, uniform classification of processes of ageing does not exist yet, and potential immortality is proved only for a hydra (Cnidaria vulgaris) (Mart´inez, 1998). Caleb Finch (Finch, 1990) proposes an original typology of senescence organisms from rapid to gradual to negligible. He introduced the term "negligible senescence" to mean "senescence too slight to be statistically distinguishable from zero with the sample sizes at our disposal". That includes non-senescence, of course -- truly zero correlation between age and risk of death. The minimal criteria are offered (Finch, Austad, 2001) for reference of a concrete species in this category: (1) no observable increase in age-specific mortality rate; (2) no decrease in reproduction rate after sexual maturity; and (3) no observable age-related decline in physiological capacity or (4) disease resistance. Such subjects should grow old so slowly that to fix age changes would be practically impossible. Except for a fresh-water hydra to them carry, for example: a lot of species of a genus Rockfish (Sebastes) (Leaman, Beamish, 1984; Cailliet et al., 2001; Munk, 2001); fresh-water Blanding's Turtle (Emydoidea blandingii); a painted turtle (Chrysemys picta); a significant part of wood forms of vascular plants (Finch, Austad, 2001); and also sea-urchin sea who can live vaguely long, being reproduce at any age, and the is more senior, the more actively (Ebert, Southon, 2003). Patnaik (Patnaik, 1994) includes into species with negligible senescence to the crocodiles and (Kara, 1994) - tailed amphibians rather plausibly, that species with negligible senescence are more numerous. It is possible that in the near future in this category will carry many species of bivalve, lobsters (Homarus) and birds.
SPECIFIC ATTRIBUTES OF "IMMORTAL" ORGANISMS
The hydra (Cnidaria vulgaris) concerns to one of most close situated at the root basis of a phylogenetic tree of group of multicellular animals: - coelenterates. Brien (Brien, 1953) informed for the first time about potential immortality of this organism and the fact of potential immortality has proved by (Mart´inez, 1998).
The hydra has a simple structure: - a tube generated from approximately 20 cellular types, being products of differentiation of three stem cell (SC) lineage with unlimited ability to self-updating: two epithelial and one interstitial (Campbell, 1965, 1967a). Amazing feature of a hydra - dynamics of a tissue. Epithelial cells of a wall of a body continuously stay in mitotic cycle and as though flow from the middle of a body by his ends, constantly moving or upwards to a head, or basal to vegetative buds, or to a bottom. Cells of a hydra have very short life span. Not dividing differentiated cells are replaced in a body of a hydra within 20 days (Campbell, 1967b). Thus, the specialized cells carry out strictly certain function, and have the limited viability. Age-related changes in these cells, capable to affect functioning of an organism, are prevented by their fast change with newly generated cells. Probably, this ability also is the reason of potential immortality of a hydra. Nevertheless, varying external conditions, it is possible to achieve ageing and from a hydra (Comfort, 1979; Lamb, 1980). At adverse change of temperature or structure of water cell fission is slowed down, the hydra grows old and perishes, i.e. depending on conditions of environment potentially not growing old organism can be in growing old or in not growing old condition (Khalyavkin, 1998), that depends exclusively on the external reasons.
Species of bony fishes. At fishes, mainly fast or gradual ageing reminding ageing of mammal is observed. Nevertheless, a number of species, for example genus Sebastes shows not ageing behavior (Guerin, 2004). At old individuals Danio rerio it is not revealed congestions of granules of lipofuscin in cells of a muscular tissue, the high level of activity of telomerase in cells of somatic tissue from embryo conditions at least till 93 years is observed. Authors explain these phenomena as at this fish growth and cellular proliferation occurs for life (Klapper et al., 1998; Kishi et al., 2003).
FROM IMMORTALITY TO SELF-DESTRUCTION. THE VECTOR OF EVOLUTION OF HERBACEOUS PLANT.
At Gymnospermae and dicotyledons among metasperms the adult tree consists from secondary thickened stalk (trunk) with a secondary branching, a root, leaves, and reproductive organs, thus a trunk and a root - constant organs and exist for life. Other organs are short life span. The trunk and a root of a tree are formed primary and secondary meristems – tissues in which division of poorly differentiated cells generates the new specialized cells. They form leaves, lateral buds, flowers and other bodies, and also provide increase in the sizes of a tree. Activity of meristems is shown during all life of a plant. Therefore wood plants continuously produce and lose a vascular tissue, leaves and flowers and do not show attributes of ageing though rate of growth can be reduced with the years. The death of a tree occurs as result of achievement of the limiting sizes incompatible with viability or the external reasons: wreckers, shading, etc. Wood plants - the most long-living organisms. Maximal life span (MLS) of the majority of them does not exceed 700 years, but there are also such species, with MLS estimated in millenia: for example, a bristlecone pine (Pinus longaeva) - more than 4 thousand years; giant sequoia (Sequoia gigantea) - more than 2.5 thousand years; Fizroya cupressoides - about 2 thousand years; juniper (Juniperus turkestanica) - about 1.3 thousand years (Vaganov et al., 2000). As well clones as naturally arising, and regrafted (subinoculation) cultural wood plants, within millenia do not lose the juvenile qualities that gives to them features of boundless longevity. The clone of (Lomatia tasmanica), for example, has age of 43 thousand years (Lynch et al., 1998).
On A. Takhtajan (1964, 1966, 1970), wood species - the most primitive within the limits of the taxons and all variety metasperms conducts the beginning from primitive wood forms. Early herbaceous plants were trees, which during the further evolution by a somatic reduction have given rise to bushes and to various grasses. Their propensity to neoteny allowed them during evolution to pass easily from primary immortal wood forms to annual or shortly living grassy forms which as a matter of fact are the wood sprouts which have received ability to reproduction. Grassy, especially annual plants, have serious advantages before trees. They have short life cycle, early maturing and as result - fast alternation of generations, that finally allows them faster evolve. On B.F. Vanyushin (2001), the destruction of a grassy plant is controllable by hormonal phenoptosis: at least monocarp plants so finish a life.
Thus, the core of evolution of herbaceous plants went from potentially immortal wood forms to short living grasses. This tendency is traced for the majority of families dicotyledons.
TRANSFORMATION OF RADIAL GLIA CELLS IN ASTROCYTES – REASON FOR POSTMITOTICY OF THE MAMMAL BRAIN AND IT IS POSSIBLE, THEIR AGEING
Among phylogenetic branches of vertebrates not growing old species occur at fishes, tailed amphibians, turtles, and it is possible, at birds. At the same time any not growing old theriomorphic animal species, neither in the paleontologic annals, nor among nowadays living mammal is unknown.
At mammal MLS varies from 3 years at the mouse (Mus musculus) till 211 years at the Bowhead whales (Balaena mysticetus) (George, Bada, 1999). Thus ageing with the extremely similar pathophysiology is observed at all species (Lamberts et al., 1997). The arthritis, atherosclerosis, change of the hormonal status, menopause, osteoporosis, vascular abnormality, deleting of a teeth, graying and balding, a cataract, accumulation of intercellular collagen, increase in quantity of lipofuscin in cells occur at all investigated species. In the certain sites of a brain there are similar change of structures and functioning of neurons (Morrison, Hof, 1997). These facts allow to assume, that the reason of ageing has arisen somewhere at the beginning of mammal evolution.
Among vertebrates postmitotic brain is the unique phenomenon that occurs only at mammal. Today there is no interpretation of physiological function of this attribute.
Researches XVIII - XX centuries have shown an opportunity of reparative and physiological regeneration of a nervous tissue of fishes, amphibians and reptiles (Polezhaev, 1968; Barres, 1999). However the higher vertebrates- birds and mammal, apparently, have lost ability to regenerations of a nervous tissue. But physiological regeneration of a nervous tissue of higher vertebrates - a debatable question, especially concerning mammal. In a brain of adults mammal neurogenesis nevertheless takes place, but in strictly limited zones from which new neurons migrate and are incorporated also in strictly limited parts of a brain. These zones are rudiments of neurogenic zones of embryo brain.
The largest of these germinal regions in the adult brain is the subventricular zone (SVZ), which lines the lateral walls of the lateral ventricles. Neural SC produce neuroblasts that migrate from the SVZ along a discrete pathway, the rostral migratory stream, into the olfactory bulb where they form mature neurons involved in the sense of smell. The subgranular layer (SGL) of the hippocampal dentate gyrus is another neurogenic region; new SGL neurons migrate only a short distance and differentiate into hippocampal granule cells (Lennington et al., 2003). Due to these facts the opinion prevails, that except for olfactory bulbs and hippocampus, new neurons normally are not updated in a brain of adult mammal individuals (Eriksson et al., 1998; Barres, 1999; Gould et al., 2001).
Long time was considered, that birds have a postmitotic brain, but (Goldman, Nottebohm, 1983; Paton, Nottebohm, 1984) show, that in a brain of birds neurons are produced in ventricular / subventricular zone where persisted neural SC into adulthood, and then migrate along fibers of RG on a long distance, mainly filling up a pool of neurons in a telencephalon (Goldman, 1998).
It is shown also a presence of well advanced radial network in a brain of adult birds (Kalman et al., 1993). Therefore, the fact of participation of RG cells has been recognized during migration of newly generated neurons, and that RG is kept in those areas of an adult brain, where proceeds neurogenesis and migration of neurons (Goldman, Nottebohm, 1983; Alvarez-Buylla et al., 1987, 1990; Alvarez-Buylla, Kirn, 1997).
These and similar facts became the basis of a hypothesis that RG cells are precursors of neurons both in embryogenesisе, and at adult vertebrates. Really, RG cells can be precursors of a part of neurons of a brain and participate in posttraumatic reparation of a spinal cord of amphibians and salamanders (Margotta et al., 1991), and also in a cortex of a brain of reptiles (Molowny et al., 1995; Font et al., 2001). Therefore is conventional, that at fishes, amphibians, reptiles and birds RG not only is kept, but also produced neurons up to the end of a life (Weissman et al., 2003).
Peculiarity of neurogenesis and his relation with apoptosis features are found out from adult bony fishes (Zupanc, 1999). The brain of these fishes possesses enormous potential for the production of new neurons in the adult brain. So, at Apteronotus leptorhynchus during 2 h it is produced about 0.2 % of the total population of cells in the adult brain (Zupanc, Horschke, 1995).
Quantitatively of mitotic active cells of a brain are distributed approximately so: 25 % from them are in the telencephalon, diencephalon, mesencephalon and rhombencephalon. The others of 75 % of such cells are located in proliferative zones of a cerebellum which represent remnants of embryonic proliferation zones (Zupanc et al., 1996). The conclusion has been made, that the cerebellum of adult bony fishes cerebellum during adulthood most closely resembles the mammalian cerebellum during its development shortly before and after birth. After migration in a place of final localization many of the newborn neurons remain alive for extremely long periods and, most likely, for the rest of the fish’s life (Zupanc et al., 1996, Ott et al., 1997). This long-term survival, together with the continuous production of new cells, leads to a permanent growth of the entire brain. While the body mass of the fish increases from 1 g to 16 g, the total number of brain cells approximately doubles from 5x107 up to 108 (Zupanc, Horschke, 1995). The ability of bony fishes, and probably all fishes, to generate new cells in the brain during adulthood is paralleled by their enormous potential to posttraumatic neuronal regeneration after injuries (Meyer et al., 1985; Waxman, Anderson, 1986; Stuermer et al., 1992; Zupanc, 1999). The path caused by the stab wound becomes gradually reduced over the period following the lesion, until, several weeks after the injury, it finally disappears. Signs of inflammation, cavitation and scarring do not occur (Zupanc, 1999). Restoration of a nervous tissue is reached by the cascade of processes, including a production and a direction of migration of new neurons to a place of damage by RG fibers (Zupanc, Clint, 2001). Presence of extensive zones of neurogenesis at adult individuals, the facts of radial migration and long-term existence (alive) of newly generated neurons are confirmed and for other species of bony fishes (Zupanc et al., 2005).
As researchers could not find out pyknotic nuclei and establish the period during which the quantity of cells in CNS reduce, it was considered, that cell death had been thought to be absent from the brain of fish in stages beyond embryogenesis (Fox, Richardson, 1982; Crapon de Caprona, Fritzsch, 1983; Waxman, Anderson, 1985; Fine, 1989). But it have shown by researches (Soutschek, Zupanc, 1995, 1996), that in many brain areas, including the prepacemaker nucleus (Soutschek and Zupanc, 1995) and the cerebellum (Soutschek and Zupanc, 1996), a large number of cells undergo apoptosis. The density of apoptotic cells is significantly higher in places of final migration, than in the corresponding proliferative zones, implying that cell death may mainly be involved in the regulation of the cell number of the newborn cells after they have reached their target areas. On the basis of this fact the conclusion has been made, that, probably, one of functions of apoptosis - to eliminate new neurons which after arrival on a place of final localization have failed to join in function chart of CNS[1] (Soutschek, Zupanc, 1996).It is interesting, that with the years at bony fishes the quantity of apoptosis events on a mass unit of a nervous tissue decreases (an age-dependent reduction in apoptotic events). As a whole about half of young cells is exposed to apoptosis, and other part lives up to the end of a life of a fish, and the most part of the survived cells is differentiated in neurons (Zupanc, 2006).