From Weismann's theory to present day gerontology 1889-2003.

From Weismann's theory to present day gerontology--Weismann's theory was based on the concept that through natural selection the division potential of somatic cells become finite thus limiting the regeneration of the soma and the life span of the organism. Indeed, the somatic cells of some animals have a finite division potential but what became apparent is that the implications for aging are more complex. Experiments showed that at each cell division the genetic information received by each daughter cell differs; cells are this way progressively modified through division creating a functional drift that is responsible in part for the continuous modifications going on in the organism from its very beginning to its extinction. Comparative biology showed that the finite or the infinite division potential of somatic cells has a complex connotation with developmental characteristics of the respective organism with implications for longevity that are far from being understood.

The biology of conformation in the regulation of the senescent and transformed cell phenotypes.

The cytoskeleton and the composition of the cytoplasmic membrane of normal somatic cells are modified during proliferation in vitro. The loss of the proliferative potential during serial divisions is due in part to these structural modifications that induce a decline in the cell conformational flexibility. During viral transformation, the changes in the affinity of the cell to its matrix and to neighboring cells increase the cell migratory capability maintaining the conformational flexibility; this way the cells can proliferate to densities where normal cells stop dividing. Cell proliferation, the transformed phenotype, and differentiation could be modulated by changing the electric charge of a substratum. Results support the view that the biology of conformation is crucial for the expression of these cell properties.

Neoplastic disease through the human life span.

Cancers are different diseases that start and evolve each in its own manner, and trigger variable responses from the organism depending upon the neoplastic process under way and upon the physiopathology of the organism. The clinical incidence of the different cancers is spread through the human life span, with regional differences for each cancer: for many cancers the incidence is increasing at younger ages. More than half of the cancers become clinically manifest during the second half of the human life span and their frequency increases with age, but their natural history starts way back at earlier ages. The data suggest that the late manifestation is the result of the accumulation of events through time rather than of aging. Interestingly, late in the human life span the incidence of neoplastic disease declines. Is this due to the cohort of late survivals naturally resistant to the development of neoplastic processes, or to the characteristics of the last 'window' of the human life span? The evolution of neoplastic disease is the result of pre- and postnatal aggressions suffered by the organism, individual susceptibility, and developmental changes that evolve continuously from the beginning to the end of the human life span. The identification of the causes of the incidences of the different cancers through the human life span will help to understand both neoplastic disease and aging of the organism.

Relevance of in vitro studies for aging of the organism. A review.

Cell culture in vitro has been widely used to study aging at a cellular level. The criticisms that have been raised to the use of this experimental system are due to incorrect interpretations of the results obtained, and to ignorance of the physiological development of the human organism through its life span. The cell culture methodology has yielded fundamental knowledge concerning how a cell is modified through division, how this creates a change in cell function, and the consequences it has on cell interactions.

Ups and downs of aging studies in vitro: the crooked path of science.

Different approaches using cell culture techniques to study the biology of aging are critically described. Most of the studies concerned the relationship between cell division potential and aging. The growth potential of cells is fundamental for aging of the organism, since it relates to phenomena such as the regeneration of tissues, wound healing, the immune response, and stem cell renewal. Unfortunately many experiments were misinterpreted disregarding the physiology of the mammalian organism. The terminal postmitotic cell, on which most research has been concentrated, seems irrelevant for aging of the organism. Nevertheless, some experiments yielded important contributions to the understanding of the biology of cell division. Future research should ascertain such interesting suggestions as the terminal differentiation hypothesis of the human fibroblast life cycle. It is important to elucidate the significance of the increased number of postmitotic cells in pathological processes. A neglected area should be further explored: the relationships between structural modifications of the cell, decreased probability of activating energy barriers, and decline of the division potential.

Markers of 'cell senescence'.

In the current literature cells that have finished their proliferative life span in vitro and have reached a terminal post-mitotic state are called senescent cells. This definition originated from the belief that the irreversible non-dividing state has a relationship with aging of the organism. Attempts have been made to find markers of the so-called senescent cell in order to detect their presence in vivo in donors of different ages. One marker which was supposed to demonstrate an increase of post-mitotic cells with aging is a marker of a long resting phase whether reversible or irreversible. Other markers suggest that the postmitotic cell does not increase with aging of the organism, that it is irrelevant for aging, that it is found in an increased number in pathology, and that the term senescent cell is a misnomer that should be used only in an operational manner.

Markers of 'cell senescence'.

In the current literature cells that have finished their proliferative life span in vitro and have reached a terminal post-mitotic state are called senescent cells. This definition originated from the belief that the irreversible non-dividing state has a relationship with aging of the organism. Attempts have been made to find markers of the so-called senescent cell in order to detect their presence in vivo in donors of different ages. One marker which was supposed to demonstrate an increase of post-mitotic cells with aging is a marker of a long resting phase whether reversible or irreversible. Other markers suggest that the postmitotic cell does not increase with aging of the organism, that it is irrelevant for aging, that it is found in an increased number in pathology, and that the term senescent cell is a misnomer that should be used only in an operational manner.

Genetics of ageing.

The classical arguments favouring a genetic basis of ageing are reviewed emphasizing the questions that remain unanswered. Genes cannot be the sole genetic determinants of ageing. Mendel's paradigm cannot anymore explain all the results recently obtained. Different aspects of the organization of the genome must also play a role in ageing. The functions of the largest part of the human genome remain unknown. Moreover the different genetic theories of ageing are based on natural selection. However, other paradigms are being proposed that can complement or replace Darwin's paradigm. They are based on the spontaneous organization of complex systems. They must be considered in the reappraisal of the ageing phenomenon.

[Genetics of aging]. / Génétique du vieillissement.

The classical arguments favouring a genetic basis of aging are reviewed emphasizing the questions that remain unanswered. Genes cannot be the sole genetic determinants of aging. Mendel's paradigm cannot anymore explain all the results recently obtained. Different aspects of the organization of the genome must also play a role in aging. The functions of the largest part of the human genome remain unknown. Moreover the different genetic theories of aging are based on natural selection. However, other paradigms are being proposed that can complement or replace Darwin's paradigm. They are based on the spontaneous organization of complex systems. They must be considered in the reappraisal of the aging phenomenon.

Proliferative cell senescence, transformation, and the recombination potential of the genome.

Fibroblast cell populations maintained in vitro display a different probability of escaping proliferative senescence and to transform. Observations at the cytogenetic level suggest that the long-term doubling potential of these cells is directly related to the potential for continuous chromosome rearrangements.

A growth inhibitor implicated in the growth arrest of human fibroblasts.

When quiescent human fibroblasts are induced to divide, the sugar composition of a growth inhibitory glycoprotein is modified. The kinetics of the incorporation of glucosamine in the growth inhibitor follows the kinetics of cell growth. It increases as cells approach quiescence and declines when cells initiate proliferation. The results suggest that the modification of the sugar composition of this glycoprotein is coupled with the variation of its inhibitory potential and this way to the initiation and the arrest of cell division.

The last mitoses of the human fibroblast proliferative life span, physiopathologic implications.

Normal human fibroblasts, after exhausting their proliferative life span, enter a post-mitotic stage where they remain metabolically active. It has been suggested that this is a terminal differentiation process. During the last mitoses of the cell population proliferative life span, sudden events take place in the genome consisting of deviations from the semiconservative distribution of DNA between sister cells, decondensation of heterochromatin, reorganizations in the high order DNA structure and the presence of extrachromosomal circular DNA. These events could correspond to the 'quantal mitosis', the last mitosis where cells become irreversibly committed to differentiation. The identification of the ultrastructural characteristics of the terminal cell allowed for the first time to ascertain the presence of these cells in a tissue in vivo. The terminal cell obtained through serial proliferation in vitro, was found only in pathological states. A cell with some, though not all of the characteristics of the terminal in vitro fibroblast, was present in vivo in normal skin in an amount unrelated to the age of the donor.

The implications of the 'hayflick limit' for aging of the organism have been misunderstood by many gerontologists.

Many gerontologists have been misdirected by the conclusion that the decline in the division potential of some cell compartments during aging is due to the increase in nondividing cells. Terminal postmitotic cells are called senescent cells although there is no evidence that they have any implications for aging of the organism. In an experimental system, Hayflick found a drift in cell functions created by proliferation, which is of relevance to the aging of the organism. Experimental evidence suggests that the presence of terminal postmitotic cells in excess in the tissues is associated with aging-related pathological states.

Chaos in DNA partition during the last mitoses of the proliferative life-span of human fibroblasts.

We have followed with autoradiography the course of DNA synthesis and with cytofluorometry the partition of DNA during mitosis, through the different phases of the life-span of human fibroblasts. Towards the end of the proliferative potential of the cell population, DNA synthesis was disturbed during the late part of the S period. The DNA content of metaphases and of anaphases had a normal Gaussian distribution during the whole proliferative life-span of the cell population. At the very end, however, when cells entered the post-mitotic phase, the distribution of DNA content deviated from the normal Gaussian probability, becoming significantly skewed.