Primary fibroblasts and other primary, untransformed cell types can undertake only a limited number of cell doublings in vitro. The number of doublings is correlated with the age of the donor of the cells, and also with the lifespan of the donor species. It is possible that this in vitro limit on cell doublings is the cause of organismal aging; however, the cause of the limit on total cell doublings is entirely unknown. We have recently discovered that as human fibroblasts age, their chromosomal telomeres get shorter and shorter, with no apparent limit to this shortening. It is possible that some chromosome ends lose all of their functional telomeric sequences, and it is this loss that causes the permanent cell cycle exit of senescent cells. Thus, telomere loss could be the ultimate cause aging. We plan to examine the structure and loss of mammalian telomeres with aging, to investigate the mechanism of telomere maintenance in germ cells and immortal cells, to isolate and characterize human telomerase (the enzyme responsible for telomere maintenance), and to try and see whether there is a cause-and-effect relationship between telomere loss and aging. Whether or not telomere loss is a cause of cellular senescence, the experiments proposed will provide valuable information on the structure and maintenance of human telomeres.
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