Molecular aspects of the relationship between cancer and aging: tumor suppressor activity during cellular senescence.

Normal cells cultured in vitro lose their proliferative potential after a finite number of doublings in a process termed replicative cellular senescence (Hayflick, 1965). The roles that growth inhibitory tumor suppressors play in the establishment and maintainence of cellular senescence have been reported in many different systems. The Rb and p53 tumor suppressors are examples of growth inhibitors that lose the ability to be regulated and are constantly activated during senescence. Other proteins that inhibit the initiation of DNA synthesis in early passage fibroblasts and that link the action of tumor suppressors with the cell cycle machinery, are also expressed at higher levels in senescent cells. For example, the increased expression of the cyclin-dependent kinase inhibitor p16 may contribute to arresting the growth of senescent cells. Identification and characterization of additional genes encoding growth inhibitors that are upregulated in senescent cells, such as the recently isolated p33ING1 protein, should provide a better understanding of the "aging program" that ceases to operate in the generation of immortal cancer cells.