Cellular Aging: Basic Phenomena

Skin fibroblasts from pairs of monozygotic twins show no significant difference in replicative life span within each pair, but do show such differences among pairs. In heterokaryons, which are formed by the fusion of two different cells, the nonproliferative phenotype of senescent cells in culture is dominant over normal proliferative cells and over immortalized cells, but not over immortalized variants having high levels of DNA polymerase α(DNA pol α) or those transformed by DNA tumor viruses. There are numerous reports documenting the presence of inhibitors of DNA synthesis in senescent cells, although the nature of these inhibitors is poorly understood, and whether any of them plays a causal role in senescence is unclear. The idea that senescent cells actively make an inhibitor of DNA synthesis, however, is supported further by the observation that expressible RNA derived from senescent fibroblasts, when microinjected into proliferation-competent cells, can inhibit their entry into DNA synthesis.

Some of the most compelling evidence in support of a genetic component for cellular senescence has been the finding that introduction of particular chromosomes into immortalized cells causes them to acquire a senescent, or at least a nongrowing, phenotype. Evidence that the cessation of proliferation is a programmed phenomenon is seen in studies that used SV40 large T antigen to produce a reversible escape from cellular senescence. This evidence suggests that senescence confers at least two distinct mortality states.

Genetic influences over the process of cellular senescence would necessarily be reflected in reproducible changes in gene expression. The list of molecular markers of senescence in culture has dramatically increased as the result of examining genes isolated from selective libraries and monoclonal antibody pools. Remarkably, the number of genes isolated by these methods includes those involved with the ECM, secretory proteins involved in growth-factor-mediated function, differentiation and shock proteins, inhibitors of DNA synthesis, and genes of unknown function.