Médecine & Longévité最新文献

In the invitation to write this article, I am asked to describe my “…contributions… to cell aging and the telomere story”. My research on the phenomenon of cell senescence began more than 50 years ago. From that time until today, the work done on this subject in my laboratory, and that of hundreds of other researchers, can only be described in the allotted space by a few generalizations and even fewer details. From the birth of cell culture technology in 1907, it was believed that all cultured cells, if provided with the proper conditions, would replicate indefinitely. Fifty-three years later, we overthrew this dogma by finding that, in the best conditions, normal cells have a finite capacity to replicate and that only abnormal or cancer cell populations can replicate indefinitely. We interpreted these findings to impact on our understanding of the aging process. If, as had been thought prior to our work, that normal cultured cells released from in vivo controls can replicate indefinitely, then age changes could not have an intracellular origin. Our findings demonstrated that, on the contrary, age changes do have an intracellular origin. The hundreds of changes that were subsequently found to precede the loss of replicative capacity have been interpreted to be age changes and the finitude of replication to be an expression of longevity determination. Age changes are the result of the inexorable dissipation of energy that occurs in complex biomolecules and that, unless repaired, causes their dysfunction. The positive balance of repair and synthetic processes over accumulating dysfunctional substrate molecules shifts after reproductive success to favor the increase in more dysfunctional molecules over repair capability as the repair processes succumb to the same Second Law of thermodynamics. The processes that control longevity, or how long repair and synthesis processes remain functional and retain their balance over dysfunctional molecules, are governed by the genome. Hence, the information that governs longevity determination is sexually transmitted whereas the aging process is a stochastic or random process governed by the laws of probability that are embodied in the Second Law of thermodynamics. Our search for the location of the molecular mechanism that controls the number of cell, or DNA replications, that occur in normal cells ended with our finding that the mechanism was located in the nucleus. Years later, and as the result of the confluence of studies done by others in several unrelated fields, the molecular mechanism was discovered. It was found that telomere attrition governs the limit on DNA replications in normal cells and that the expression of telomerase can circumvent this limit, thus explaining our discoveries of the phenomena of normal cell mortality and cancer cell immortality.

La découverte du vieillissement cellulaire par L. Hayflick et son analyse au niveau cytogénétique par Macieira Coelho, auteurs des deux premières revues de ce numéro spécial consacré à ce sujet, a ouvert une nouvelle voie dans l’étude du vieillissement et ont créé un modèle in vitro qui a permis d’aborder au laboratoire des problèmes que pose ce phénomène complexe qu’est la sénescence cellulaire et son extrapolation de la cellule à l’organisme pour élucider son rôle dans le vieillissement de l’individu et dans l’émergence des maladies qui l’accompagnent. Cette complexité fait l’objet de la revue de B. Carnes et de ses collègues (1992) [34] et constitue aussi le fond de nos réflexions qui suivent les trois précédentes. Nous aborderons en particulier les mécanismes et les conséquences fonctionnelles du vieillissement cellulaire et de son rôle dans le vieillissement des tissus et des organes. Cela nous amène à analyser au niveau cellulaire et moléculaire les maladies qui accompagnent le vieillissement, surtout les maladies cardiovasculaires et les tumeurs malignes. Ces deux classes de pathologies sont en effet essentiellement responsables du décès des personnes âgées. Dans notre discussion et conclusions, nous confronterons l’essentiel de nos connaissances acquises au niveau fondamental avec les données classiques pour préciser le rôle du vieillissement cellulaire dans les pathologies liées à l’âge.

The discovery by L. Hayflick of cell aging in culture and its cytogenetic analysis by A. Macieira-Coelho, authors of the first two articles of this special issue of Médecine et Longevité devoted to this subject, opened a new way for the study of aging by creating an in vitro model enabling the experimental study of problems related to the complex phenomenon of cell-senescence and its extrapolation to the whole organism in order to elucidate its role in aging of individuals and the emergence of age-related diseases. The complexity of these problems is the subject of the review by Bruce Carnes and his colleagues (1992) [34]. It is also at the basis of our reflexions following the three preceeding articles. We shall discuss in particular the functional consequences of cell aging and its role in tissue and organ aging. This will lead to the study of the cellular and molecular mechanisms involved in age-associated diseases, essentially cardiovascular and malignant pathologies. These two pathologies are responsible for the demise of most seniors, at least in industrialized countries. In our discussion and conclusions, we shall try to confront results acquired at the fondamental level with “classical” data at the clinical level in order to define the role of cell aging in age-associated pathologies.

La culture de cellules in vitro a montré que la plupart des cellules normales ont un potentiel de prolifération limité et il a été suggéré que celui-ci est l’expression du vieillissement à l’échelle cellulaire. On a testé si le potentiel de division serait en relation inverse avec l’âge de l’organisme mais les résultats n’ont pas été unanimes. L’éventuelle relation directe du potentiel de division cellulaire avec la longévité des espèces respectives n’a pu être confirmée. Finalement, il a été établi que l’implication de ce phénomène de vieillissement cellulaire n’est pas l’épuisement du potentiel de division mais le fait qu’il y a une limite. Chaque division cellulaire entraîne des modifications au niveau moléculaire tendant vers cette limite, qui sont cumulatives et créent une dérive fonctionnelle contribuant au vieillissement de l’organisme. Cette dérive contribue à la réorganisation permanente qui a lieu dans l’organisme de la naissance à la sénescence et explique plusieurs phénomènes que l’on observe au cours du syndrome du vieillissement.

The cultivation of cells in vitro has shown that most normal human cells have a limited proliferation potential. It was suggested that this attribute is the expression of aging at the cellular level. Attempts were made to test if the remaining division potential is inversely related to the age of the organism but this could not be ascertained by all the attempts. The putative direct relationship of the division potential with the longevity of the respective species could not be confirmed. What finally became apparent is that the implications for aging of the organism is not reaching the non-dividing end point. Extensive studies have shown that at each division cells suffer modifications at the molecular level, which are cumulative and originate a functional drift. The drift contributes to the permanent reorganization that proceeds from birth to senescence, which explains many of the manifestations of the syndrome of aging.