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Ku80 is important in the repair of DNA double-strand breaks by its essential function in non-homologous end-joining. The absence of Ku80 causes the accumulation of DNA damage and leads to premature ageing in mice. We showed that mouse embryonic fibroblasts (MEFs) from ku80−/− mice senesced rapidly with elevated levels of p53 and p21. Deletion of p21 delayed the early senescence phenotype in ku80−/− MEFs, despite an otherwise intact response of p53. In contrast to ku80−/−p53−/− mice, which die rapidly primarily from lymphomas, there was no significant increase in tumorigenesis in ku80−/−p21−/− mice. However, ku80−/−p21−/− mice showed no improvement with respect to rough fur coat or osteopaenia, and even showed a shortened lifespan compared with ku80−/− mice. These results show that the increased lifespan of ku80−/− MEFs owing to the loss of p21 is not associated with an improvement of the premature ageing phenotypes of ku80−/− mice observed at the organismal level.