Genetic and Environmental Modulations of Chromosomal Stability: Their Roles in Aging and Oncogenesis

Abstract

The primary objective of this review is to suggest a major role of cytogenetic pathology in the genesis of both the neoplastic phenotype and the senescent phenotype of aging mammalian organisms. It is hypothesized that allelic variation at a number of genetic loci that have the potential to modulate various types of chromosomal mutation could account, in part, for species-specific variations in maximum life-span potentials and the times of onset of characteristic age-related neoplasms. As a corollary to this proposition, attention is directed to the potential importance of environmental clastogens and aneugens as both oncogenic and "gerontogenic" agents. By way of introduction, a series of definitions of our subject material is given (aging, oncogenesis, proliferative homeostasis, point mutation, chromosomal mutation, epimutation, mutagens, clastogens, aneugens, gerontogens). There follows a defense of the view that there is a tight coupling of abnormalities in proliferative homeostasis (including atrophies, hyperplasias, benign neoplasias and malignant neoplasias) with intrinsic biological aging. This view differs from those of other authors who either: 1) believe that, to qualify as a bona fide component of aging, the phenotype in question (in this case, neoplasia) must be "genetically programmed" or 2) insist that the rate of development of the neoplastic phenotype should parallel species-specific Gompertz kinetics for the survival of the population of organisms. After briefly reviewing the classification of chromosomal lesions, we consider evidence for constitutional genetic determinants of chromosomal stability, oncogenesis, and some other aspects of the senescent phenotype, both with respect to interspecific and intraspecific differences. The discussion will include the recent evidence characterizing a human segmental progeroid syndrome (Werner's syndrome) as a deletor mutator strain. A summary of research on environmental chemical clastogens and aneugens is given, showing both discordances and concordances of such assays with assays for point mutagens. An analysis of the literature indicates that there is no statistical evidence for the positive correlations when substances showing effects only at comparatively high concentrations (greater than 1 mM) are excluded from the analysis. Brief mention is also made of the roles of viral agents and ionizing radiation in the genesis of chromosomal mutations. Finally, some possible pathogenetic mechanisms common to chromosomal mutagenicity, oncogenicity and gerontogenicity are considered, including chemical free radicals (active oxygen species), DNA transposition, DNA amplification, DNA glycation, virally induced cell fusion, posttranslational modifications of centromeric and mitotic spindle proteins, and alterations in the metabolism of telomeric DNA.