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A.V. ARTEMOV



UNIVERSAL CONCEPT

of

SENESCENCE

unexpected view of the problem

through

corneal endothelium

ББК 28.703+54.102

А861

УДК 611.018.74.002.25:616.1-003.87

Artemov A. Universal concept of senescence (unexpected view of the problem through corneal endothelium). –Odessa:Interprint, 2008.

ISBN 978-966-2139-05-1
Despite their variety all reputed theories of senescence imply the age-related degeneration of the cell as the imprescriptible clause of senescence. Indeed, from the point of cellular pathology the senescence of tissues, organs and organism on whole can not take place without aging of separated cell as the fundamental structure of higher organisms.

The concept presented here demolishes this stereotype.The senescence of our organism takes place without the age-related deterioration of cells. This paradoxical assertion became possible only with the help of modern knowledge of medicine and biology, the special place among which occupies the notion of apoptosis.

Based on the knowledge of general pathology and the unique possibility which the study of cornea gives us, the author comes to the conclusion that the senescence is the special natural process of stochastic disintegration of cellular associations where there is no place for senescence of the cells.

For the wide audience of physicians and biologists


А861

Артемов А.В. Универсальная концепция старения

(неожиданный взгляд на проблему через роговичный эндотелий).-Одесса: Интерпринт, 2008.

Текст. парал.на англ.и рус.яз.



ISBN 978-966-2139-05-1
При всем своем разнообразии существующие теории старения исходят из того, что первичным звеном возрастной дегенерации является клетка. Действительно, с точки зрения клеточной патологии старение тканей, органов и организма в целом,на первый взгляд, не представляется без старения клетки как фундаментальной структуры высших организмов.

Предлагаемая автором концепция разрушает этот стереотип. Старение нашего организма происходит без старения клеток его составляющих. Это парадоксальное утверждение стало возможным только в свете современных знаний медицины и биологии,особое место среди которых занимает представление об апоптозе.

Основываясь на достижениях общей патологии последних лет и уникальной возможности, которую дает изучение роговой оболочки, автор делает вывод, что старение это особый процесс естественного стохастического распада клеточных ассоциаций, где нет места для старения клеток.

Для широкого круга медиков и биологов



ББК 28.703+54.102

УДК 611.018.74.002.25:616.1-003.87
© A.V.Artemov, 2008

© А.В.Артемов, 2008

ISBN 978-966-2139-05-1
From the author
This monograph is the more detailed exposition and ground of ideas that arouse during the previous work [2]. The mentioned work was devoted to the analysis of problems related to cornea donorship and it was not specially dedicated to the study of question of senescence.

However, when the main work was completed, while writing the section related to the biological age of cornea an author unexpectedly went further from the primary outlined questions.

The original interpretation of mechanism of senescence arose up spontaneously and it was beyond the scope of the specific ophthalmology question. So it demanded the special attention to this theme.

While stating the basic ideas of the new concept of senescence the author does not touch upon many other adjoining themes. In particular these are the topics of the problem of carcinogenesis, some questions of immunology and pathology on the whole.

The above mentioned themes , undoubtedly, will

find new interpretation, if we acknowledge that senescence is the stochastic disintegration of cellular-tissue associations and not the result of accumulation of intracellular breakages. So, the new understanding of cardinal gerontology problem will extend the horizon of researches in medicine and biology.




« It is difficult to seek for a black

cat in the dark room, especially,

when one there is not present»

(from Confucius)

INTRODUCTION:

the general look at the problem
The subtitle of the book may seem to be somewhat strange. Indeed, what kind of connection can there be between the specific ophthalmology theme and the fundamental problem of senescence?

Nevertheless, the posterior epithelium of cornea (corneal endothelium) that first and foremost became the object of intensive study in ophthalmology in connection with clinical necessity and request of corneal transplantation can play the role of the Rosseta stone and give us the unique possibility to decipher the mechanism of senescence.

The analysis of facts accumulated by specular microscopy in relation to the age-dependent changes of corneal endothelium, and also taking into account other information of general pathology, allowed the author to formulate the original concept of senescence that is presented to your attention.

The fruitfulness of reductionism as methodological principle is being discussed for a long time in science, but still the sphere of its application is not found.

However, yet from the school course of mathematics it is well known that the complicated algebraic expression with numerous components will be the easy one of it simplified to the minimum number of components.

In our case the unicity of cornea is that with the example of its posterior epithelium we can get the possibility to look into the process of senescence with the most simplified kind.

It is difficult to find any other tissue system in the organism of the man that would allow to trace changes that are going on with cells and tissue on the whole not only in vitro but also in vivo during the specified space of time.

If due to numerous tangled intertwining events in the whole organism or in its independent organs and tissues it was not possible to find the verge, which distinguishes pathology introduced by illness from changes the source of which is only time, it became possible to see with the example of corneal endothelium.

Is it possible to discover the nature of senescence by phenomenological principle? Once the discovery of X-ray and radio-activity has resulted in the finding of fundamental laws of nature.

However, broadly speaking, the phenomenon of senescence causes no doubt. And its different manifestations are studied very intensively not only from biological but also from physical and chemical points of view.

Nevertheless, now the most complete definition of senescence sounds too vague. Thus, according to the encyclopaedic definition - a senescence is the natural biological process of gradual decline of functional and adaptation possibilities of organism on the whole, and also its organs and tissues that result in development of different diseases and death.

So, the main achievement of modern medicine in gerontology since the creation of cellular theory is the acceptance of senescence existence as the special type of pathological process not related to casual factors but depended only from time.

It is necessary to notice that the similar understanding of senescence was already present as early as ancient medicine. Cicero wrote about it: “Senectus ipse morbus”.

There is an old aphorism: senescence brings the person to precipice into which he is pushed by illnesses. In this metaphorical utterance we can see the obvious hint about the difference between two types of pathological processes: disease and senescence.

However, on the way of search of this elusive verge the researchers were caught by aporia that is even far more difficult than the well-known Zenon’s paradoxes.

Indeed, how can we distinguish what pathological changes of cells are conditioned by age and what changes by a morbific agent? In fact any pathology is related to deviation from the normal structure and function.

The absence of pathological influence (agent) could be the criterion of age-dependent change. However, if we follow the concept of prion infections that is dramatized by some scientific groups practically any degenerative process can be bound with the presence of elusive prions. Probably it is not mere chance that the walkthrough of prion conception brought the author to the unexpected look at the mechanism of senescence.

It is necessary to notice that the possibility to approach face to face to the creation of this concept arose up during the work over problems that had no direct relation to gerontology theme.

Only one single topic was indirectly touched with the question of senescence. It was about the connection between quality of corneal transplant and the age of a donor.

If we initially set the global problem about the creation of senescence concept, at once we get into the tangle of great number of facts and phenomena. As a rule, it was possible to see only the general contours of the phenomenon through this scientific web.

Indeed, never before gerontologists have shown particular interest in the decision of the specific practical task of determination of aging of some concrete tissue or organ. The researchers were attracted by the finding of the decision of the problem on the whole. Probably, they supposed that it is possible to see the essence of aging with the help of the whole idea not with the help of some specific parts.

Here it seems appropriate to remark the classics of philosophical idea of the 19th century : «a practical necessity is able to move science in advance more quickly than ten universities».

Thus, while the problem of senescence was tried to resolve scholastically ( in the global scale), the essence of this process remained veiled over philosophical generalizations. When the task was formulated in the concrete practical area, its decision appeared as the manifestation of general biological regularity.

***


As far back as the last century there is the unpublished dispute between the representatives of physiological and morphological medical directions about the fact who has priority in comprehension of essence of pathological processes.

Biochemistry, molecular biology, immunology and others medical and biological disciplines have considerably extended our comprehension of organism and its function at the turn of the 20-21th centuries.

Histochemistry, electronic microscopy and immunochemistry allowed us to get to the structure of living tissue at the level of nanometer and even single biomolecule .

However, how all this aggregated knowledge is capable to present us with deeper understanding of entity of senescence?

Realizing the scantiness of any medical speciality, researchers while stating their points of view on senescence always aspired to use the knowledge from all scientific disciplines mentioned above.

However, in fact, such synthesis is the mechanical association of knowledge, the type of the compendium of gerontology. Every decade the new page has been added to its with expectance when quantity will turn into quality.

One of the main discoveries of the last decade was the notion about apoptosis that was the foundation of the new concept of senescence. Among the number of metaphorical comparisons and mystifications, aspiring to present apoptosis as the cell suicide or its informative death, it is needed to pay attention to one very important detail. Researchers engaged in the problem of senescence in the last century lacked this one potent scientific fact.

Thus, researchers always bound death of a cell with pathological influence.The study of apoptosis mechanisms showed that a cell can die being in the physiological state. And the main factor of such death is the loss of cellular contacts. This kind of apoptosis is sometimes called the “ anoicosis”.

It is obvious that modern pathology bring us to one of the major mechanisms that are situated in the basis of a number of pathological processes that were formerly called degenerative. Degenerative diseases were usually viewed as age-dependent pathology and their pathogeny has been adjoined with the mechanism of senescence.

The analysis of the problem of prion infections, to which the author appealed in connection with the study of transmission of donor’s pathological processes in corneal transplantation resulted in the new understanding of degenerative processes.

Thus, through elusive protein-destroyers (prions) the author caught the universal mechanism of the unusual type of pathological processes.

There are two choices.One of them is related to doubtful confession of protein as a infection agent that is capable to autoreproduction and to destructive influence like a viral or bacterial agent.

This way leads to the revision of wide circle of molecular-biological knowledge which became the

achievement of the second half of the 20th century.

Thereby it is necessary to notice that any new concept or theory which does not specify or explain the set of positions of contiguous specialities, but vice versa from them to repudiate the principles that are out of doubts, is very questionable.

But there is another way that doesn’t require hasty revolution in modern notion of medicine and biology.

It is necessary to procced from the idea that protein can not be the infection agent, but can be the pathogen. These ideas took roots during the last century. We must utillize them to provide the explanation for unusual proteins.

Dramatizing the concept of prion, its supporters do not want to look at the nature of this pathological process within the framework of existent knowledge. Protein as pathogen is able to cause great number of various changes. Some of this systemic changes are related to the immunological response of organism for protein as an antigen.

Wherein prion aggression is vivid for some researches the author suggests to try to see ordinary immunological mechanism, where a protein shows the abilities of unusual antigen. The singularity of immunological reaction antigen vs antibody consists in the fact that it is directed against the special type of proteins that provide intercellular contacts.

There is no sufficient information to endow protein with ability of destruction of the whole tissue system and on the basis of this fact to revise not only microbiology and virology but also molecular biology.

It is not good to forget the property of protein as an antigen to start the immunological reaction.Also it is known, that similar reaction can be directed against antigens similar to proteins of organism.

So, antibodies blocking the function that is vitally necessary for cellular associations support the mechanism of destruction of the tissue system. That is the reason why (without inflammation and other ordinary pathological reactions) the invisible destruction of the whole tissue system occurs.

The supporters of prion infections have seen destructive work of this mechanism mainly in the example of some pathologic processes in central nervous system.However, we can found analogical processes in all tissues of organism.

In experiments with prions the researchers reproduced only specific variant of pathology related to destruction of intercellular contacts.In nature this pathological process takes place constantly and its main initiator is the time.

Thus, the idea of apoptosis that is projected on prion concept brings us to the unexpected understanding of senescence mechanism. The mechanism, in the analysis of which there is no necessity to seek for the cell damage.

While craving for understanding of senescence we tried to penetrate the cell as deep as possible to see micropathology caused by time. However, many facts bring us to the idea that time destroys not the cell, but cellular associations. In other words, it is not the cell that ages, it is the tissue.



***
In the ancient aporia by Zenon «Achiles goes after a tortoise» the Greek philosopher tries to tangle the opponent by way of substitution the physical question of motion with the mathematical idea of infinitesimal.

The ancient scientist causes a clash between two different ideas and tries to prove the absurdity:” light-footed Achilles is not able to go after a sluggish tortoise”.

Contemporary aporia was created by researchers of 19-20 centuries and it interfered with the discovery of the mechanism of senescence.

The researchers could not find the mechanism of senescence because they were seeking it where it was not present. You had to reject the idea that had no actual confirmation. Neither the cells on the whole nor its autonomous components don’t age.

Indeed, proofs of some phenomena may seem to us as assertoric because they turn to be obvious by virtue of their perception. Thus, the indisputable fact of senescence of organism we transmitted to cell, shutting out the possibility of the degradation of the unit without pathological changes of its parts.

However, such logic does not reflect the general regularity and it can not be applied as universality. In fact, there are some known phenomena in nature when the destruction of unit is not accompanied with damage of its separate parts.

In my opinion, the creation of this concept was conditioned by the successful set of circumstances. Foremost, it was the work over the problem of preservation of donor cornea.

The prior experience of the twenty years of work in general and eye pathology was projected by the author towards problems of the Eye Bank. It allowed to look at the problem of preservation of cornea from another point of view.

For the specialist in pathology questions of preservation of donor cornea can appear as the uninteresting ones according to the scientific point of view. Indeed, in everyday practice this work is related to the search of modes and mediums for preservation, where knowledge of a biochemist or a physiopathologist,but not of a pathologist (morphologist), has more priority.

At first I had the same attitude. Therefore my basic attention was directed to more abstract questions.So, two circumstances caused particular interest.

Why in the regime of cryopreservation ( at the temperature of liquid nitrogen) embryonic, stem or tumor cells can be saved without restriction , but it is impossible to save effectively the corneal transplant (donor cornea)?

So, the impregnated ovule preserved in liquid nitrogen is able to provide the development for the whole organism. But corneal transplant that was received in the same way, as a rule, is incapable to provide a transparency of cornea that seems to be more primitive medical and biological task .

Why at the temperature of enzymatic zero (about +4 degrees Celsius) it is impossible to save the viable corneal transplant more than for 2-3 days , although proliferous (viable) cells in the same transplant can be saved at least for two weeks?

These examples suggest that viability of cells and viability of tissue are provided with different factors. Functionally nonviable tissue can consist of viable cells.

Clinicians and pathologists do not run into this paradox during their clinic and dissector work. But for specialists who work with cadaver donor material this biological oxymoron becomes obvious.

The analysis of data, received from transplantology, allows to approach closely to non-standard understanding of the mechanism of senescence. The same mechanism, where there is the senescence of tissue without damaging (ageing) of cells.

The final decision arose up in the process of search for age-dependent limit for donor cornea. It seems that this concept of senescence arose out of ophthalmology not by mere chance. Other specialists, who are busy dealing with problems of corpse donorship, could not engage themselves in such practical problem.

It is related to the fact that organ transplantology demands very strict criteria to age of donor material. It is not accepted to use corpse organs from donors more who were older than 40-50 years.

In addition, it is not really possible to find other objective tests of functional suitability of heart, nephros or liver beyond the scope of the known pathological processes. The transplantologists just screen elderly donors and decide transplantology problems within the age limit.

Keratoplasty is not only the first successfully transplantology operation but also one of the most widespread transplantology operations. The scales of keratoplasty are not comparable with transplantations of other vital organs such as heart, liver or nephros. The necessity of a corpse cornea is so large that it is not always possible to meet them within the framework of young donorship.

It is also important to notice that keratoplasty practice has shown the high functional eligibility of cadaver corneas received from donors aged 60-80 years. And after the fact, when ophthalmologits in the last quarter of the past century came to unanimous opinion about the leading role of posterior epithelium (endothelia) of cornea in providing its transparency, there appeared the major objective test for the estimation of quality of corneal transplant.

If the corneal graft has the low density of endothelial cells (usually this limit is determined on the line of 2000-2500 cells/mm) the surgeon discards it regardless the donor age and external (native) safety of cornea. This requirement is clear for ophthalmotransplantologits and does not cause any objections.

At the same time, it is sometimes possible to meet with the dubious attitude of ophthalmologists toward the use of transplants from elderly donors.

Certainly, there is the dependence of endothelial density from the age: this index is, as a rule, lower with elderly donors. However, for example, if there will be the identical density of endotelial cells in corneal grafts from donors aged 40 and 70 years,are there any grounds to give priority to the transplant from the younger donor?

Physicians of different specialities known very well that senescence goes on unevenly. A young man can have an old heart and vice versa, although the general tendency is certainly known.

Is it possible to assess corneas from a young and elderly donor as age- equal if they have the identical density of endothelia? Such assumption is fully reasonably. In fact, we assume that one man ages faster than the other one. So, we can rather expect the absence of coincidence in the ageing of autonomous organs and tissues.

The author proceeded from this thesis when he tried to prove the groundlessness of discredit of corneal graft by the reason of age without any calculation of endotelial density.

Not having found other arguments according to the explanation of the functional waning of corneas from old donors (except for the density of endothelial cells), the author paid attention to constancy and evenness of the density loss of endothelial cells during life.

Thus, there are no other regular age-dependent changes in the cornea. The synthesis of all these facts resulted in the unexpected conclusion: the loss of cells is solely the unique mechanism of senescence.

The fact that cornea endothelia demonstrates to us is inherent in all tissues of organism, i.e. the universal mechanism of senescence.

The reader who hasn’t gone through the whole brain work that preceded this conclusion can see this fact as the strange tautology.

Indeed, nobody denies that cells are constantly lost, but what is the connection to the mechanism of senescence? One can see the opposite argument at once: cells are lost because they age and (or) damaged.

However, even without all statistical information, I considered it possible to assert that cells are lost due to the special mechanism which at that moment united already in my consciousness within the framework of general concept.

We could see from the new concept that if cells don’t age but are lost due to postulated stochastic mechanism, that was inherent in the tissue system (association of cells), the process of disappearance of cells must happen faster when the person is younger than in the old age.

In other words, the more cells are in an association (tissue), the more of them are lost. If cells had aged and been lost in this connection, the rate of their disappearance would have grown with age.

Certainly, the main concept idea was based on my own observations that were related to age-dependent density of endothelial cells of cornea. However, the special statistical analysis was not conducted beforehand. Thus, the concept appeared not from statistical calculations, but, on the contrary, the concept demanded statistical confirmation in one of major details.

All information is known, apparently, about cornea endothelia as about the object that is accessible not only to histological study using total sections but also to visual observation in vivo by means of a spectral microscope.

Thus, it is known that endothelial cells in the interval from 20 to 100 years are lost evenly (approximately 0,6 % in year). In other words, the rate of the cells’ disappearance is not increased with age. The amount of the extinct cells in the absolute calculation, vice versa, is diminished towards the old age, as well as the concept predicts. Indeed, statistics, with the certain degree of metaphorical ideas allows to talk about the fact that senescence occurs faster when the person is young than in the old age.

This statistical fact is the basic argument on behalf of the new idea of senescence, although the author only implied its existence in the process of creation of this concept.

The mentioned statistical data, along with other information about cornea endothelia, was already known as early as the last century.However, there was no attempt to interpret them somehow.It is possible that it gives them large virtue. In any case, it is impossible to reproach the author in the statistical garbling with the purpose of confirmation of the new concept.

Moreover, it is possible to assert with large confidence that being engaged in studying of corneal endothelium only and having received the mentioned statistics, the author also would not have paid attention to it.

Probably, it is necessary here to mention retrospectively the Mendelian segregation (3:1), which with all its statistical importance and uncommonness, was not noticed be scientific circles for a few decades.

Therefore, understanding that no statistics will replace the penetration in essence of the phenomenon, the author will try to zoom in the concept, which elements were described above, as much as possible.


Chapter 1

Theories of senescence

It is possible to find the very interesting quoting of Demokritos in gerontological literature: «Old age is the damage of the whole organism with complete uncrippledness of its components».

It is possible to see here the intuitional-empiric understanding of idea that old age is unconnected with the accumulation of damage. To some point it is almost like the new concept of senescence that is offered in more than two thousand years after the great ancient Greek thinker.

However, unlike the sagacious prediction of atomistic device of the matter the Demokritos’s opinion about the essence of senescence remained to be in the shadow.

Indeed, at the level of anatomic research that was possible in the days of Ancient Greece, some pathological changes in vitally important organs of an old man could not be found, but his life stopped.

However, in the subsequent theories of senescence this idea did not come into consideration. Vice versa, the search of the destructive changes caused by time was the priority.

Certainly, the old age is connected with destructive processes. But these changes were looked for only at level of autonomous parts (cells). The senescence of the whole (organism or tissues) without any damage to its separate parts (cells) seemed to be impossible. But that was exactly the hint by Democritus.
***

The search for the mechanism of senescence was accompanied by interlacing of clinical, pathophysiological, chemical and biological approaches.

The first approach is related to exaggeration of independent clinical syndromes and physiopathology phenomena and acknowledges them as the trigger of senescence.

Some theories adhere to the leading role of hypophysial-adrenal system, hormones of thyroid, sexual hormones in ageing.

These ideas, related to such names as Steinach, Voronoff, Lorand, Parhon were cultivated on the peak of some discoveries in physiology and clinical medicine and carried not only the peculiar understanding of mechanism of senescence, but also active attempts of influence on it.

Thus, in the first half of the past century the grafting of sexual glands and the hormonal extractions with the purpose of «rejuvenation» of a man became famous. However the clinical doubtfulness of these geriatrics innovations became obvious soon, and the second half of the last century was characterized by experimentally-theoretical approach, but is not search of wonderful methods of rejuvenation.

At the beginning of the second half of 20th century the theory of cumulative stress by Strehler and Mildvan was widely discussed. The idea of these authors had something common with the famous concept of Gans Selye which had many followers among pathologists and physiologists.

These authors proceeded from the fact that not only negative but also physiological reactions on external influences result in the exhaustion of functional systems of the organism. This theory explained the sudden (unexpected) death during physiological senescence as an inadequate answer for standard stress situations.

However the mechanism of development of stress exhaustion remained hidden. In spite of the explanation of sudden death in the old age, this theory evaded the question about the concrete mechanism of senescence.

In addition, unlike senescence, stress is not the universal phenomenon for all forms of life. This is also peculiar to many other theories of senescence that exaggerate the role of isolated physiopathology mechanisms, which only take place at more higher level of biological development.

Above all things, the neurogenic theories of senescence that present now the historical value have the similar drawback (Vogt, Parhon, Marinesco). Accumulation of information about the leading role of the nervous system on the whole and its autonomous centers (e.g. reticular formation or hypothalamus) in regulation of vital functions of integral organism caused quite a bit of interesting ideas in gerontology.

However, there are number of circumstances against the superiority of changes in the central nervous system in the mechanism of senescence.

Even for a man, for whom neuropsychic processes are fundamental in vital functions, degenerative changes in the cerebrum quite often considerably fall behind in time from senile pathologies in other organs.

The nature of integrative processes in the nervous system during senescence reflects more frequently the changes that are going on at the periphery but it doesn’t predetermine them. This opinion was offered as early as in the 19th century by Bichat. He marked the priority of centripetal changes above the centrifugal ones during regressive processes in the central nervous system.

Ordinary cases of high level of intellect and mental abilities with expressed signs of ageing of soma in old men only prove this idea.

The perverted afferentation during ageing results in violation of interrelation of organism with the environment. It generates psychological and somatic discomfort in the old age and also numerous diseases. However, this thesis of supporters of neurogenic theory of senescence reflects only the state of senile organism, but no way it points out towards the mechanism that leads to it.

Thus, acknowledging the important role of humoral and neurogenic factors in ageing, we can not relay on them for the explanation of mechanism of senescence.

Also it is necessary to remember that primitive organisms are involved in senescence too, despite the absece of the endocrine or high-organized nervous systems.

Other concepts of senescence that associate this process with the change of fundamental structures of all living organisms regardless the level of organization don’t have this drawback.

It seems fully logical to examine senescence as the process that originates at the level of elementary parts that present the whole thing. Thus, age-dependent changes in regulator systems become only the private manifestation of general mechanism of senescence.

Thus, we treat the cell as the main unit on which all pathological process in the whole organism are locked .

The theory of cellular pathology that became one of the major conceptual decisions in the medicine of the 19th century determines that all pathological processes in the organism take place with the participation of cells.

Consequently, the senescence as the pathological process must meet this requirement of cellular pathology too. Thus, one began to examine the participation of a cell in the mechanism of senescence in terms of its primordial ageing.

Apparently, the straightforward compliance with the principle of cellular pathology has continued in substitution of notions that resulted in one-sided interpretation of cell participation in such uncommon pathological process as senescence.

But there is the distinction between two conditions : the participation of the cell in the pathological process and the pathological change of the cell itself. However, the extrapolation of existent notions about the majority of pathological processes, where cell participation is practically the pathological change of the cell itself, in one or another way , formed the stereotype of methodological approach to the study of senescence.

This stereotype eliminated the idea about the possibility of senescence of the whole organism or its tissues without the cell senescence.

However, when some researchers studied the cell without any relation to gerontology problems, they found numerous facts that directly or indirectly doubted the senescence of the cell.

***


Metalnikov and Wudroff were one of the first who at the beginning of the last century got thousands of generations of one-celled organisms. They came to the conclusion that ageing is not universal quality of the organized matter.

Later the idea about cell immortality was supported by Alexius Carrel in experiments with cultivation of embryonic myoblasts.

Trying to justify the basic dogma of theory of senescence many researchers began to talk about inadequacy of existence of one-celled and multicellular organisms.

Prokaryotes and one-celled organisms do not age and die as during permanent divisions they pass on the genome and soma to next generations. Thus, there is disappearance of individuality without senescence and death. For metazoons the loss of individuality is always accompanied with death as the inevitable result of senescence.

However, due to this philosophical rhetoric that tries to save the situation with the thesis about the closeness of such phenomena as «loss of individuality» and «death of individuality» the real (but not concept-abstract) sense of the phenomenon of immortality of one-celled organisms is lost.

The vague excuse for possible mixing of notions of «death of individual» and «endless development in nature» shows the unwillingness to acknowledge the main idea.

One-celled organisms demonstrate us the sense of this idea: the mechanism of senescence does not lock itself in genome (DNA). In other words, at the level of macromolecules that determine both the individuality and all the following it is capable to reproduce, it is impossible to see fatal predetermination of death.

If there had been such predetermination, the chain of generations would have been interrupted because of destructive influence of time. In fact, between the divisions of one-celled organisms and prokaryotes there are sometimes long (for years) cessations during which the genome had to accumulate pathogenic potential.

But maybe, the immortality of genome is preserved only at the level of one cell, and disappears in the metazoon? Certainly, it is possible to idealize this problem even further. It is possible, for example, to talk about the appearance of special «genes of death» in metazoons. But if everything depends on the presence of some genes the senescence ceases to be the universal and inevitable phenomenon. If we withdraw, replace or improve the gene the senescense will be avoided.

Really, at such level of understanding of the problem it will be possible to see the horizon of immortality at metazoons. However, most researchers do not take into account this approach by intuition.

The absolute majority, taking into account the concealment of mechanism of this process, considers senescence as the inevitable result of existence of metazoons that conjugated with some self-contradictions in their vital functions and organization.

Such contradictions are hardly eliminated on principle unlike the unfavorable layout of genes.They are the essence of existence of multicellular organization and disappear together with it.

The presented reasonings are the retrospective estimation of problem from positions of the already created concept. They did not precede its creation; however, these ideas allow to see the lacks of concepts that considered the senescence of cells and its internal elements as the main link of senescence of metazoons.

***
The theory of cellular pathology already in the 19th century began to find the application in the explanation of mechanisms of ageing. It is interesting to note that first theories were not related directly to the search of the origins of senescence inside the cell.

Thus, Spenser and Roux explained senescence as the result of contradictions between separate cells.Cellular antagonism that is determined by individual nutrition requirements of cells could become the reason for their chronic starvation. Muhlman supported this idea at the beginning of the 20th century.

As it is possible to notice, here we see senescence as chronic damage of cell, but the reason of its development is seen at the system level,i.e. it does not originate from the cell.

The intense development of cytology and biochemistry in the first half of the last century moved aside these ideas as being incongruous according to the accumulated facts about compensatory and adaptation possibilities of cell’s metabolism.

From this moment most ideas that exploit the theory of cellular pathology began to be based on the presence of mechanism of senescence in the cell itself.

On the peak of the promising discoveries of electronic microscopy and molecular biology there were no reasons to search for ageing in contradictions of cellular association.

It seemed that more deep penetration into vital functions of the cell, to the level of macromolecules and ultrastructural elements, would allow to see those age-dependent defects which slipped out from researchers at the level of light microscope.

In particular, Cowdry talked about these expectations in the middle of the last century.He directly noted that insufficient knowledge of ultrastructure of the cell one does not allow to conclude about the reason of senescence.

The theories of primary cellular senescence became popular at the beginning of the second half of the last century (Cowdry,Strehler,Smith).

Some authors explained the senescence of the cell by the institutional instability of its structures; others stressed the connection between life-span of a cell and level of its differentiation. At this time the thesis became popular that senescence of a cell is the atonement for its differentiation.

However, many facts doubted this supposition. In particular, the highly developed organisms, the cells of which gained the greatest degree of differentiation along the evolutional way, achieved the longest life-span.

In addition, the concept of differentiation by itself is very ambiguous. Thus, if the cells of germinal system and cambial (stem) cells follow the path of differentiation then the narrow scopes of life are defined at once.

The term of life on the segment of terminal differentiation for such cells is calculated by days and weeks. At the same time,one of the most differentiated photocepters of retina and neurons of cortex keep up to their functions as long as the organism lives, i.e. in different occasions to one hundred years and more.

Some authors notice fairly that in certain terms senescence and death of cells in the integral organism can be the same permanent phenomena as differentiation, cambial renovation and regeneration. In other words, senescence and death of separate cells are needed for the organism and are the constituent part of its physiology.

If we still talk about the age-dependent changes of cells it is necessary to do it in terms of senescence of organism on the whole. The resume of this interesting idea we can find on the pages of one monograph: “the age-dependent changes of separate cells are derivatives from senescence of the whole organism, but they are not the reason for it”[6].

However, this idea that is very closely contiguous to the concept presented here would not lead us to the concrete understanding of mechanism of senescence.

In addition, at this level of knowledge, when this thought has been spoken out, the probability of it was very small.

Probably here we can see the intuitional comprehension of an outstanding pathologist about the mechanism of senescence. In his opinion, this mechanism works somewhere in the middle between the whole( an organism) and the part (cell).

If we look closely at the theories of the last century we will not find the complete rejection of the principle: «senescence of organism is the senescence of cells». There are only attempts to shift aside from the concrete answer under circumstances when real displays of senescence in the cell were not discovered.

Thus, one idea appeared that there is the legion of interactive factors between the organism, its systems, organs, tissues, cells and the environment .

In these terms the priority of cell in the senescence of organism is not so obvious. Therefore, it was noticed a long ago that «cells age together with the organism but die after it».

Thus, as early as in the middle of the last century the doubts have been uttered in regard of the leading role of a cell in the mechanism of senescence.

However, these doubts that are fully reasonable in connection with the absence of the established facts about cellular age-dependent damage did not play any role in the search for the real mechanism of senescence.

The cytological and ultrastructural findings in the cells of the old organism that were well known already in the beginning of the second half of the last century did not point out towards the mechanism of senescence. In addition, they did not have any clear specific of age and there always was the question about the priority of these changes in the old organism.

Also there was the possibility to object that discovered changes are displays of general regulator violations in cells of the old organism, i.e. they are the indirect manifestations of system dysregulation.

In this connection, in the background of the attempts to find the intracellular manifestations of senescence, theoretical generalizations, as a rule, have been locked at the system level.

Trying to understand the mechanism of senescence, the researchers, as a rule, shifted aside from the elementary (cell and its macromolecules) to the estimation of age-dependent manifestations at the level of organism on the whole. In other words, not being able to find sources of senescence, researchers concentrated their attention on the obvious displays of senescence while creating one or another concept.

However, it is necessary to note that idea of cellular senescence was very popular in the 1960-1980s of the last century. Mainly,this idea was initiated by researches of Haiflick and Moorhead[]. Using the certain methodical approach they succeeded to show the limitedness of proliferation of practically all of zygoid somatic cells in terms of in vitro cultivation.

The limit determinated by them ( approximately 50 divisions) was soon successfully projected on the molecular-genetic conceptions. At the beginning of 1970s it was showed theoretically that this limitation is related to the mechanism of the work of enzyme of DNA-polymerase during the process of duplication of DNA.

Thus, the site of DNA-polimerase attachment that has the extent approximately to 20 nucleotide sequences is not copied and will be lost with every new division.

Thus, during 50 divisions a segment of 1000 nucleotides will be lost and that corresponds to the extent of terminal areas of chromosome that are called “telomere”. After this point the work of DNA-polimerase’s mechanism will become impossible and cells’ division will stop.

This conception, perceived in the beginning rather ambiguously, in the middle of 1980s gets the experimental confirmation : m-RNA-telomerase complex that is accountable for renewal of telomere was discovered.

It was shown that the replication possibilities of cells are related to the activity of telomerase. Telomerase became the peculiar marker of constantly renovated cells (embryonic or stem cells) and also the malignant cells.

Finding out the role of telomerase in the mechanism of cell’s renewal is undoubtedly one of the most important moments. It is exactly the absence of telomerase activity in the cells of differentiated tissues that correlates the potential instability of cells to the apoptosis, and that we will discuss in details in the next chapter.

Taking into account in more details the research works of Haiflick that served as the beginning for the clarification of the role of telomerase’s mechanism in limiting the number of cellular generations, we must note that these findings do not specify in any way the real mechanism of senescence as other investigators sometimes tried to offer.

The phenomenon of Haiflick outlines the term of existence of the proliferated cellular associations (cellular cultures). From these positions it is possible to talk about the exhaustion of proliferative potential of the cellular system but not about the senescence of differentiated tissue. The differentiated cells do not have telomere from the beginning of formation of this cellular system to the end of its existence.

***


Completing this brief review of various notions of senescence, it is necessary to notice that there were not too many solutions of this problem in the last century.It can be seen clearly in the background of impressive achievements in understanding of mechanisms of many diseases and pathological processes.

This dissonance seems very strange. Why with such grandiose progress in understanding of pathological processes that occured in the past century our comprehension of mechanism of senescence did remain practically at the level of common philosophical generalizations?

All these facts suggest that the gist is not in the profoundness or largeness of our knowledge related to biological substrates and processes but in the principle of estimation of mutual relations between cells and the whole organism.

In other words, estimating the huge volume of knowledge, accumulated by medicine and biology during the past century, it is possible to suppose that it is necessary to find the cipher but not another fact for the discovery of the mechanism of senescence.Just like this Champollion in the 19th century made ancient Egyptian hieroglyphs talk.

Reasonably considering the cell to be the obligatory participant of senescence, researchers in the investigation of mechanism of age-dependent changes constantly tried to attribute them to the most intimate intracellular processes.

However, in the background of numerous philosophical generalizations and metaphorical comparisons, it is necessary to remember that sometimes even a wall that is being destroyed in course of time due to wind and natural cataclysms leaves the undamaged rocks in its foundation. Similarly our organs and tissues lose the viable cells while ageing. Undoubtedly, the amazing biological phenomenon of apoptosis brings us to the understanding of this idea.



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