The long term objective of this investigation is to investigate the molecular basis for cellular aging and the role that gene regulation has in that process. These experiments will use cultured human fibroblasts derived from normal individual and aged in vitro, from donors with syndromes of premature senescence, and from aged donors that have been obtained from the Human Cell Mutant Repository (maintained by the NIH-NIA). The project focuses on the regulation of two enzymes, collagenase and stromelysin, whose enhanced expression is correlated with in vitro senescence. We propose to use biochemical and molecular techniques to analyze the regulation of those enzymes, as a function of extracellular autocrine inducers and at the level of DNA binding proteins. The results of this investigation could have broad implications and provide a mechanism through which the pleiomorphis process of aging can be regulated by a few active factors.