Putative mechanisms responsible for the decline in cancer prevalence during organism senescence.

Most scientific literature reports that aging favors the development of cancers. Each type of cancer, however, initiates and evolves differently, and their natural history can start much earlier in life before their clinical manifestations. The incidence of cancers is spread throughout human life span, and is the result of pre- and post-natal aggressions, individual susceptibility, developmental changes that evolve continuously throughout an individual's life, and time of exposure to carcinogens. Finally, during human senescence, the incidence declines for all cancers. Frequently, the progression of cancers is also slower in aged individuals. There are several possible explanations for this decline at the tissue, cell, and molecular levels, which are described here in. It is time to ask why some tumors are characteristic of either the young, the aged, or during the time of a decline in the reproductive period, and finally, why the incidence of cancers declines late during senescence of human beings. These questions need to be addressed before the origin of cancers can be understood.

Control of cell replication during aging.

The observation that human fibroblasts have a limited number of cell population doublings in vitro led to the proposal that it is the expression of cellular aging. In vitro, the proliferation of human fibroblasts terminates with a postmitotic cell which was called senescent cell. Due to misinterpreted experiments, the latter was considered the hallmark of cellular aging, although obviously we do not age because our cells stop dividing. The so-called senescent cell has been the core of the investigation on cellular aging and of the theories proposed on the subject. The search for mechanisms responsible for the postmitotic state led to contradictory results, which accumulated when the term cell senescence was used to define the growth arrest due to a variety of causes. The mechanisms believed to be causing these multiple forms of cell senescence multiplied accordingly. This was disregarded claiming that there are multiple pathways to cell senescence. Since it was thought that aging favors malignant transformation, speculations were made to find a relationship between 'cell senescence' and cancers, which led to several paradoxes. The contradictions and paradoxes should be cleared to reestablish logic and order in the field and understand its relevance for human aging.

Cell division and aging of the organism.

The capacity to regenerate cell compartments through cell proliferation is an important characteristic of many developed metazoan tissues. Pre- and post-natal development proceeds through the modifications occurring during cell division. Experiments with cultivated cells showed that cell proliferation originates changes in cell functions and coordinations that contribute to aging and senescence. The implications of the finite cell proliferation to aging of the organism is not the accumulation of cells at the end of their life cycle, but rather the drift in cell function created by cell division. Comparative gerontology shows that the regulation of the length of telomeres has no implications for aging. On the other hand there are interspecies differences in regard to the somatic cell division potential that seem to be related with the "plasticity" of the genome and with longevity, which should be viewed independently of the aging phenomenon. Telomeres may play a role in this plasticity through the regulation of chromosome recombination, and via the latter also in development.

Cancers and the concept of cell senescence.

The post-mitotic cell reached by normal cell populations after serial divisions has been regarded as the hallmark of cell senescence. It was proposed that this non-dividing cell is a mechanism of protection against malignant transformation and different approaches have been used to induce the post-mitotic state. There are contradictions and paradoxes between the concepts and the data, which are described herein. There are also contradictions between data from different laboratories that attempted to identify the mechanisms leading to the post-mitotic cell. The contradictions are bypassed with the claim that there are different pathways to cell senescence. The contradictions and the differences between the data should be explained before these phenomena can be understood.

Asymmetric distribution of DNA between daughter cells with final symmetry breaking during aging of human fibroblasts.

Human fibroblasts proliferating in vitro go through functional modifications, lose progressively their capacity to divide, and enter finally a post-mitotic state. These events are supposed to reproduce the developmental steps taking place in vivo during aging of the organism. The gradual changes occurring through proliferation are incompatible with an even distribution of the genetic material during cell division. We measured the amount of DNA on pairs of daughter cells at different population doubling levels of human fibroblasts. It was found that at each doubling in a significant fraction of cells, the distribution of DNA between sister cells is asymmetric. The cell system is in a steady state through the different phases of the fibroblast population life span; then during the last mitoses when the cells enter the terminal phase IV there is symmetry breaking with a phase transition, the cells settling into a new state.

[The biology of conformation in the regulation of the senescent and transformed cell phenotypes]. / La biologie de la conformation dans la régulation des phénotypes cellulaires senescent et transformé.

The cytoskeleton and the cytoplasmic membrane of normal somatic cells are modified during proliferation. The loss of the division potential during serial proliferation is due in part to these structural modifications that induce a decline in the cell conformational flexibility. During viral transformation, the changes in the cytoskeleton and in the affinity of the cell to its matrix and to neighboring cells increase the cell migratory capability, maintaining the conformation flexibility needed for the initiation of the division cycle. We could modulate cell proliferation, transformed phenotype, and differentiation 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.

The decline of the clinical incidence of cancers during human senescence.

Neoplastic growth occurs from the very beginning to the end of the human life span, with a predominant age span for the clinical incidence of each cancer. Most cancers are diagnosed during the second half of human life span, but their natural histories start much earlier than their clinical manifestations. The clinical incidence declines after ages 75-80 years. The histology, the evolution, and the distribution of the frequency of the different cancers during the human life span suggest that neoplastic growth is a dynamic process where new variables are continuously created, the result of the interaction of individual genetics, environmental aggressions, and the developmental stages of the human life span. Data suggest that in many instances tumor growth can be looked upon as a deviation from normal development. Mechanisms are described that can explain the decline of the incidence and the progression during senescence in terms of the changes occurring in the human organism during the last developmental stages.