In response to hyperproliferative signaling elicited by transforming oncogenes 
some normal human cells can enter replicative senescence as a tumor defense 
mechanism. We recently found that human fibroblasts or endothelial cells with 
genetically-engineered reduction of proto-oncogene c-Myc expression switched 
with an increased frequency to a senescent state by a telomere-independent 
mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent 
kinase inhibitor p16(INK4a). The same regulatory circuit was triggered upon 
exposure to mild oxidative stress. These findings point to the existence of a 
mechanism for monitoring hypoproliferative signaling, whose function may be to 
limit the proliferation and accretion of physiologically compromised cells. This 
mechanism may be another example of antagonistic pleiotropy leading to 
organismal aging.