THE MOLECULAR-BIOLOGY OF PROLIFERATIVE SE NESCENCE

Clones of non-transformed human cells are mortal, that is, the cells d ivide only a limited number of times before they approach a state of p roliferative senescence. This state has long been regarded as a cellul ar model of organismal aging or as aging ill vitro because of its clos e relationship to the aging process of the donor of the cells. The und erlying molecular mechanisms of this particular aging process have onl y been recently understood and are reviewed in the present paper. Cell division is accompanied by progressive telomere shortening, which is due both to properties of the replicative apparatus (the ''end-replica tion problem'') and to oxidative damage to telomere DNA under conventi onal cell culture conditions. If shortening of telomeres reaches a cer tain critical level, it is recognized as DNA damage by the cell's ''gu ardian of the genome'', the tumor suppressor p53. Stabilization of p53 activates the well characterized cell cycle checkpoint at the G1/S ph ase boundary and blocks the cell cycle irreversibly. Two recent result s prove that telomere shortening is in fact the trigger of the checkpo int control in cellular senescence: First, acceleration of telomere sh ortening by increased oxidative stress results in accelerated prolifer ative senescence. Second, stabilization of telomere length, typically by activation of telomerase, appears to be a necessary prerequisite fo r the immortalization of cells. Proliferative senescence, therefore, s hould be understood as an important means to counteract genetic instab ility and cancer.