Our encompassing objective is an integrated, comparative study of critical changes in the structure and metabolism of human cell strains as they proceed toward senescence in culture. We shall investigate the processes associated with aging, finiteness of cell doubling capacity, and eventual death in diploid cell culture systems considered to be models for biological aging. One such system is the human lung fibroblast, WI 38; this cell strain, in various stages of cell doubling, will be the principal object of our study. However, as required, we shall study other cell types. Because changes in metabolic events within a cell may be initiated by changes in the plasma membrane, we shall study the composition, antigenic characters and metabolic activities of the membranes of cells aging in culture. Occurrence in the membranes of specific lipoproteins, glycoproteins and glycolipids will be studied in relation to age of the cell culture, as will be various marker antigens and viral receptors. The adenyl cyclase system, cAMP-dependent protein kinase, and receptors in the membrane for catecholamines and other hormones will be investigated with respect to aging. Binding and transport proteins for pertinent amino acids will be sought in the membranes of young cells making collagen as opposed to older cells that have lost this capacity. Possible factors that could turn off collagen synthesis will be investigated, including changes with age of mRNA, of tRNA's, of hydroxylation, and in distribution of ribosomes and polyribosomes. Other metabolic events possibly affected by changes in the membranes, such as the synthesis and degradation of glycogen, will be studied. An attempt will be made to establish an order of changing biochemical events as the cell culture ages, seeking connections between events, and determining the fundamental changes in regulation that could trigger off the whole process of aging.