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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. |
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