Aging is associated with a decline in cellular proliferative capacity. In culture, mammalian fibroblasts undergo a limited number of population doublings (senescence); this number generally decreases with increasing age. The mechanisms responsible for cell senescence are largely unknown. Cell proliferation is governed by environmental factors, of which polypeptide growth factors play a major role. Current evidence suggests that the defective growth shown by senescent cells is the result of an abnormality at a post-growth factor receptor site, and that some growth-related genes may be abnormally expressed in senescent cells. This proposal explores how growth factor- generated signals modulate specific genes in cultured human fibroblasts undergoing active proliferation or senescence. The genes of primary interest include the proto-oncogenes c-fos, c- myc and c-ras, ornithine decarboxylase, and two genes of unknown function (JE and JB) whose expression is growth factor-inducible. These genes probably serve different functions, and are likely regulated at different sites (pre- or post-transcriptional) by growth factor-generated signals. We will define the extent and levels of regulation by growth factor signals, and we will determine one or more post-receptor systems are altered during cellular senescence, resulting in specific changes in the regulation of certain genes. These studies are designed to provide a molecular basis on which to build our understanding of the control of cell proliferation both in early passage human fibroblasts and during cellular senescene.
