The limited reproductive life span of normal human cells in culture

It has been suggested that the limited reproductive life span of normal (diploid) cells in culture may be explained by an inevitable shortening of one or more telomeres. The hypothesis is that one of the shortened telomeres will either generate a specific signal or will invoke a DNA damage checkpoint, in either case causing that cell to leave the cell cycle irreversibly. To assess this hypothesis, I review what constitutes the limited life span of cells in culture. Careful inspection of the kinetics of the life span of diploid cells in culture has shown that the limited life span arises because a fraction of newborn cells irreversibly leave the cell cycle at each division; and this fraction of reproductively sterile cells increases steadily throughout the life span of the culture. Cell fusion experiments suggest that only a small number of genes are involved in preventing continued cell growth, but that at least two independent mutation events are required to immortalize human cells, although only one event is sufficient in some rodent species. Human genetic diseases such as Werner's syndrome indicate that the duration of the life span is also genetically regulated, and is independent of the cessation of cell proliferation.