The tumour-suppressor pathway formed by the alternative reading frame protein of the Cdkn2a locus (Arf) and by p53 (also called Trp53) plays a central part in the detection and elimination of cellular damage, and this constitutes the basis of its potent cancer protection activity1,2. Similar to cancer, ageing also results from the accumulation of damage and, therefore, we have reasoned that Arf/p53 could have anti-ageing activity by alleviating the load of age-associated damage. Here we show that genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of ageing-associated damage. These observations extend the protective role of Arf/p53 to ageing, revealing a previously unknown anti-ageing mechanism and providing a rationale for the co-evolution of cancer resistance and longevity.
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We thank M. Muñoz for mouse colony management and animal care and E. Santos for mouse genotyping. A. Matheu was funded by a predoctoral fellowship from the Spanish Ministry of Education and Science (MEC); A. Maraver is funded by the Juan de la Cierva Program of the MEC; and I.F. is funded by the Ramon y Cajal Program of the MEC. This work has been funded by the MEC (M.S. and M.A.B.) and the European Union (M.S. and M.A.B.). M.A.B. is a recipient of the Josef Steiner Cancer Research Award 2003.
Author Contributions A. Matheu and A. Maraver contributed equally to this work; A. Matheu, A. Maraver, I.F., I.G.-C., C.B. and J.M.F. performed experimental work; P.K. analysed data and assisted in editing the paper; M.S. wrote the paper; J.V. and M.A.B. co-directed research; and M.S. designed research and directed the project.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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Matheu, A., Maraver, A., Klatt, P. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007) doi:10.1038/nature05949
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