Date of Award

4-1981

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Samuel Goldstein

Abstract

To test the error catastrophe theory of cell senescence, we have developed a cell-free protein synthetic system from human diploid fibroblasts capable of translating both the synthetic mRNA, poly (u), and endogenous cellular mRNA in vitro. We have measured the fidelity of poly(U)-directed protein synthesis in extracts from a variety of cells. The results contradict the error catastrophe in several ways: - cells from subjects suffering maladies of premature aging, progeria and Werner Syndrome, exhibited error frequencies within the normal range. - cells from an old donor did not have elevated error frequency of protein synthesis. - early-passage (young) normal cells had error frequencies higher than those of late-passage (old) cells. The error frequency in one normal strain of fibroblasts declined throughout its tissue culture lifespan. Cells maintained in the post-mitotic (terminal) state, in which there was no cell selection, exhibited a constant error frequency over 16 weeks. In a series of experiments using clonal populations of cells, it became evident that the decline in error frequency as a function of passage was dependent on the clonal heterogeneity of the mass culture. In no experiment, however, could any correlation between the error frequency of protein synthesis and cellular growth parameters be made. Overall, the senescence characteristic of human diploid fibroblasts was independent of the measured fidelity of protein synthesis in vitro.

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