A longitudinal study of human age-related chromosomal analysis in skin fibroblasts

Previous chromosomal analyses related to human aging used mainly cross-sectional data on metaphase chromosomes. However, it is difficult to directly relate the cross-sectional results to the specific type(s) of chromosomal mutations possibly occurring within a specific individual with advancing age, because the unique genetic endowment of each individual for longevity might be a modulating factor. We therefore have performed, for the first time, a longitudinal study of both numerical and structural chromosome analyses of skin fibroblasts at interphase and at metaphase derived from eight donors participating in the Baltimore Longitudinal Study. We have used the FISH method with chromosome-specific DNA probes and the data on total aneuploidy of 17 different chromosomes in each of the 16 cell cultures (2 from each of eight individuals) indicate that significantly higher percentages of aneuploid cells are detected at interphase than at metaphase. Mostly, the levels of chromosome-specific aneuploidy increase with the donor's advancing age and, in most individuals, chromosomes 1, 4, 6, 8, 10, and 15 show significantly higher frequencies of aneuploidy at interphase than those of the 11 other chromosomes studied. Although the significance of relatively higher levels of aneuploidy of certain chromosomes with aging remains unclear, it is intriguing to note that some of these chromosomes, such as 1, 4, and 6, have already been assigned to harbor senescence genes and chromosome 8 is known to house the gene for Werner Syndrome (progeroid syndrome), which shows very limited proliferative capacity of fibroblasts. It is conceivable that the degree and/or type of chromosome-specific aneuploidy might have some gene dosage effects in the control of cellular proliferation and selection during aging. We also show that a combination of both interphase and metaphase aneuploidy analyses provides more comprehensive and insightful information on intraindividual cellular dynamics and chromosomal aneuploidy as a function of age. Occasionally, very small proportions of cells in two individuals showed age-related structural chromosome aberrations, such as an acentric fragment derived from an X chromosome and an achromatic gap in chromosome 7. Thus, a comparative analysis of both intra- and interindividual longitudinal studies is very useful in detecting the pattern(s) of chromosome-specific alterations with increasing age.