Delayed ageing through damage protection by the Arf/p53 pathway

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Abstract

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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Figure 1: The tumour suppressors Arf and p53 cooperate in conferring cancer resistance.
Figure 2: Delayed ageing in s-Arf/p53 mice.
Figure 3: Decreased oxidative damage in s-Arf/p53 mice.
Figure 4: Increased expression of antioxidant genes in s-Arf/p53 mice.

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Acknowledgements

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.

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Correspondence to Manuel Serrano.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Tables S1-S2 and Supplementary Figures S1-S15 with Legends. The file was corrected on 20 July 2007 (PDF 1523 kb)

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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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