Further studies on the genetic and biochemical basis of cellular senescence

Cell fusion analysis, exploiting the fact that the phenotype of immortality is recessive in hybrids, has allowed the assignment of 26 different immortal human cell lines to at least four complementation groups for indefinite division. This indicates that there are at least four sets of genes or processes involved in the mechanisms leading to cellular senescence. We have also observed alterations in gene expression accompanying senescence that induce the expression of a protein inhibitor of DNA synthesis, expression of new cell surface epitopes as identified by monoclonal antibodies specific to senescent cells, and changes in the extracellular matrix. We have yet to determine whether these changes in gene expression are casual or the result of senescence. The assignment of immortal cell lines to specific complementation groups now allow for a focused approach to identify the normal growth regulatory genes that have been modified to yield immortal cells and determine whether certain senescent cell specific patterns of gene expression continue to be expressed in immortal cells within a group. In addition, the isolation of senescent cell-specific antibodies provides for the first time the tools with which to probe the relationship between in vitro and in vivo aging.