The Limited Proliferation of Cultured Human Diploid Cells: Regulation or Senescence?

Abstract

It has been widely accepted that the limited life span of human diploid fibroblasts in culture provides a valid experimental model for the study of aging at the cellular level. In spite of innumerable investigations the underlying cause of cessation of growth is not known. Many approaches are being used to test the specific hypothesis that cells at the end of their life span produce an inhibitor of the initiation of DNA synthesis which irreversibly arrests cells in G1, rather than resulting in cell death. This implies that there is positive control of cell proliferation and that the final population of noncycling cells is in a stable state. There appears to be a basic contradiction between this interpretation of published data and the long-standing view that cells actually become progressively senescent during phase III of their growth in vitro. The DNA inhibitor theory can be criticized on a number of grounds, and there is considerable evidence that fibroblasts at the end of their life span are heterogeneous and have a very complex pleiotropic phenotype. One effect of these changes would be to prevent DNA synthesis and normal progression through the cell cycle. The conclusion is that phase III cells are indeed senescent, presumably as a result of a general failure to maintain the integrity of macromolecules and other cellular components.