Deteriorating collagen synthesis and cell ultrastructure accompanying senescence of human normal and Werner's syndrome fibroblast cell strains

Ultrastructural changes that accompanied senescence, in vitro, of six normal fibroblast cell strains were found to correspond to the morphological characteristics of a Werner's syndrome progeroid cell strain: greatly increased size of midnuclear diameters; heavy vacuolation; maturation of predominantly primary to secondary lysosomes; increase in multilobed nuclei; dilation of mitochondrial cristae; dilation of rough endoplasmic reticulum and the filling of intermembrane space with electron-dense particles presumably protein; and vacuolar accumulation of fibrous material which was later discharged into the medium. This fibrous material was produced only by late-passage fibroblasts and Werner's syndrome fibroblasts and had an ultrastructure dissimilar from that of normal collagen fibers produced by exponentially-growing cultures. The fibrous debris had a high subunit molecular weight (approx. 200000 D), an amino acid composition that included hydroxyproline, hydroxylysine, and relatively large amounts of proline and glycine, and was degraded by collagenase. This protein is believed to be a form of procollagen produced by either incorrect maturation of mRNA or incomplete processing of procollagen.