Although p53 deletion improves stem-cell function in mice with short dysfunctional telomeres, it does not enhance their overall longevity, owing to an increased incidence of cancer. In contrast to lategeneration Terc−/− p53+/+ mice, late-generation Terc−/− p53−/− (or p53+/−) mice showed increased tumour incidence and, importantly, an altered tumour spectrum76. Instead of the typical lymphoma-dominated and sarcoma-dominated tumour spectrum in p53−/− mice with intact telomeres, telomere-dysfunctional Terc−/− p53−/− mice developed epithelial cancers of the skin, gastrointestinal tract and breast, a spectrum highly reminiscent of that seen in the aged population in humans76. The impact of p53 deficiency on ageing and cancer phenotypes of telomere-dys-functional mice is in contrast to the impact of deletion of Ink4a/Arf, which encodes the cyclin-dependent kinase inhibitor p16INK4A and the p53 activator p19ARF (ref. 30). Ink4a/Arf deletion did not attenuate the degenerative phenotypes elicited by telomere dysfunction nor lead to an increase in the number of epithelial tumours. Instead, the late-generation Terc−/− Ink4a/Arf−/− mice succumbed to the lymphoma and sarcoma spectrum expected for Ink4a/Arf−/− mice, albeit with a longer latency77. These contrasting studies not only underscore how
