Some aspects of cellular aging.

Studies were carried out on cultured human fibroblasts in order to elucidate the biology of aging and the origins of age-dependent diseases. The replicative life span of cultures was inversely proportional to the chronological age of the tissue donor, and cultures derived from subjects with two inherited disorders of premature aging, progeria and Werner syndrome, had more severely impaired growth capacity. Studies on circular outgrowths whereby cell division is restricted to a circumferential rim of cells indicated that the replicative life span is controlled by a mitotic counter to a critical limit. The response of progeria cells to a hormone preparation with insulin-like activity was decreased, while in normal cells this decrease occurred as a function of passage level with a "shift to the right" of the dose-response curve. Cyclic AMP content of fibroblasts at late passage fell in response to PGE1 stimulation but rose in response to epinephrine, likely due to altered expression of genes for the receptors for each of these two hormones. This system of cultured human fibroblasts is useful in explaining various concomitants of biological aging including decreased tissue cellularity and impaired hormone and drug responsiveness.