Cellular senescence is induced by diverse means and hence thought to be mediated by multiple pathways. We show that prolonged unbalanced growth due to retardation of DNA replication elicits a senescence-like phenomenon irrespective of the cell type. In fact, modest inhibition of DNA replication by various means led to cell swelling, cytoskeletal alterations, and irregularly enlarged, flat cell shape. Such cells upregulated senescence-associated genes, and eventually lost division potential. These phenotypes, which define cellular senescence, were virtually reversed by reducing protein synthesis or blocking ERK of the MAP kinase family. These results suggest that cellular senescence is a manifestation of prolonged unbalanced growth linked with mechano transduction and can be prevented by at least two different ways. (c) 2005 Elsevier Inc. All rights reserved.