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I.R.F. / Aging news / General / 05020701

Measuring Instruments of Time in the Cells of CNS
Posted on: February 7, 2004

The central nervous system coordinates functioning of the whole animal organism. For the reason that the monitoring of biological time which is very important for the orderly performance of individual development (including the duration control of consecutive developmental events, the monitoring of continuance of state of maturity, as well as the tracking both of onset of aging and an endurance of aging as a part of organismal development), time control should be carried out, most rationally, just with participation of cells of this crucial command system of an animal organism. Different facts show in total that the brain is an initial substratum of aging, and DNA of neural cells is primary substratum of this process. It was proved that a selective irradiation of an animal brain does evoke accelerated aging in absence of a radiation disease. The irradiation of the whole fruit flies larvae did shorten the life span of the imago. Drosophila metamorphosis is characterized, in particular, by that circumstance that only nondividing cells of nervous ganglia are able to keep the label of a radiosensitizer 5-bromo-2'-deoxyuridine (BrdU) from the larval stage up to the adult state. Being administered at the larval stage, BrdU deteriorates photosensivity of an imago. Taking into account, that radiosensitizer BrdU is able to cause the accelerated, though postponed in time, radiation aging of an adult organism (that was irradiated while being a larva) and considering that such an effect can be explained only by preservation of a specified label in DNA of the CNS, Akifiev and Potapenko have concluded that the initial substratum of an imago aging was solely the DNA of nervous ganglia. They have suggested that only some minor fraction of chromosomal DNA, which does not code for proteins, is responsible for aging.

Age-dependent changes of the epiphysis that is a part of the CNS bring a significant contribution to organismal aging. Reasoning from endocrinological studies and clinical observations, Dilman and coauthors long ago drew the conclusion that the animal brain is a primary substratum of aging and, moreover, they have specified which of its compartments makes, in their opinion, the most important contribution to aging; for such a role the hypothalamus-pituitary complex has been proposed. Still more important is that in these works the concrete physiological mechanism of participation of the hypothalamus in aging has been offered for the first time. Dilman assumed that the age-dependent changes in energy metabolism are most decisive for the aging of an organism and that they are caused by the gradual raising of a threshold of sensitivity of the hypothalamus-pituitary complex to the common inhibitory signals incoming from the peripheral endocrine glands. This compels the complex to work increasingly constrained that gradually disables its homeostatic systems, triggering a number of the major pathologies of an old age. As to the primary cause of the mentioned shift in the threshold of the hypothalamus sensitivity, it remained unknown. However, now it is possible to explain that cause by the shortening of chronomeres in cells of the CNS and, as a consequence, by alteration of the chronomere-dependent levels of expression of receptors and other factors in neuroendocrinal and neurotrophic cells of a brain, which later do lead to the advent of pathologies of advanced age.

Studies in different vertebrate and invertebrate species not only unanimously testify that the brain is a pivotal organ in organismal aging. In addition, they multifacetedly confirm an especially significant role of energy metabolism of the CNS itself in aging. Mutations of Snell and Ames dwarf mice provoke the underdevelopment of the hypophysis secretion, in particular, a growth hormone, which is coupled with an energy metabolism in its operation. As it turned out, the mice with deficiency of a growth hormone live much longer than the common mice. Investigation of mutations in the nervous system of worms also yields fruits. Mutations of the genes encoding proteins of the insulin signal pathway, which operates in neurons, influence the life span of the adult animal. The most demonstrative changes in the work of a neuroendocrinal system of C. elegans, which were caused by mutations in daf-2 and age-1 genes of the insulin signaling pathway, were immediately involved in energy metabolism regulation. These mutations considerably increased the life span of the worms. A study by Wolkow and his coauthors is especially remarkable in this context. Working with daf-2 and age-1 genes coding in C. elegans respectively the homologs of insulin receptor and phosphatidyl-inositol-3-kinase, researchers used the promoters specific to the particular types of cells. They have forced an expression of the daf-2 or age-1 wild type genesin the mutant worms that do live for an especially long time just due to mutations of these daf-2 and age-1 genes. The expressionof daf-2 or age-1 wild type in muscles or cells of the intestine of mutants did not in any way change the life span. However, when an expression of the same daf-2 or age-1 wild type genes, i.e., normal genes, has been exercised in neurons, the longevity of the mutant worms appeared to be sharply reduced. This expression returns the nematode life span to the wild type that reduces the duration of their life to the "wild" norm. These experiments directly and unequivocally specify a key role of the nervous system and its energy metabolism in the life span of animals. It is hardly possible to interpret the observed effect as an unfavorable change in formation of free radicals since their production in wild type should as much as possible be compensated by a protective action of antioxidant systems. What is the actual mechanism of the beneficial effect of mutant neurons on a C. elegans life span, i.e., why does a change in their energy metabolism remarkably delay the rate of aging? This question remains unanswered.

Within the framework of the redusomal hypothesis, it appears justified to accept the existence of the dependence of regulation of the scrupting process on the features of the energy metabolism control. It is possible to admit that a decrease in frequency of the T-rhythm peaks and/or attenuation of the rate of transcription of a redusomal DNA could be coupled either simply with reduction in energy metabolism level or with a change of ways of its regulation. By the way, a calorie-restricted diet is the major among the already known ways of effective life span extension in rodents. It was shown that such diet elevates in primates and rodents the sensitivity of cells to insulin and glucose tolerance as well. This emphasizes once again the importance of the energy metabolism modulation as a geroprotective intervention. In connection with the discussed role in aging of the nervous system and its energy metabolism, it is important to mention that a calorie restricted diet promotes an increase in producing the neurotrophic BDNF factor and also the nerve growth factor as well as other substances capable of enhancing the viability of neurons. One of the ways of coordination by brain of the energy status and food requirements of an organism, and additionally, of coordination of the functioning of different biorhythms, including the T-rhythm, could be participation of the circulating factors such as, e.g., leptin. For example, it is produced at a periphery, but participates through a feedback system in regulation of the neuronal cell activity of the hypothalamus.

Thus, estimating the significance of the listed evidence from the viewpoint of the redusomal hypothesis, it is possible to assume that, under restricted undernourishment, the intensity of chronomere transcription and/or the frequency of T-rhythm bars (that is, the frequency of the acts of scrupting in brain cells) is reduced. In its turn, this favors the economy of chronomere length and, by that, increases the life span of the organism. In this context, it is possible, by the way, to reconsider the role of the energy metabolism in aging as follows. Under the redundant consumption of calories, just the accelerated exhaustion of chronomeres (due to the speeding up of the acts of scrupting), rather than the intensification by itself of the fabrication of active species of oxygen, or ROS, is the triggering factor of aging. Overeating requires the intensification of the functioning of different cellular systems, the antioxidant system including. Hence, overeating demands also enhancement of the transcription of various redusomes in order to support increased cellular activity, thus forcing redusome shortening. However, further, already at the background of pathologies primarily arising only owing to the excessive shortening of a redusomal DNA, the ROS start to be produced in excessive quantities. These excessive parasitic ROS exert a noxious action on cellular structures, getting increasingly dangerous just with further stepwise redusome reduction.

Source: Olovnikov A.M. ; The redusome hypothesis of aging and the control of biological time during individual development; Biochemistry (Mosc) . 2003 Jan;68(1):2-33.
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