Abstract
The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.
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Acknowledgements
We thank L. Chin, N. Sharpless, S. Artandi, F. Muller, V. Walsh, S. Colla, M. Ugolotti, M. Jaskelioff, D. Liu and A.-J. Chen for discussions and critical reading of the manuscript. A. Protopopov and E. Ivanova kindly provided the chromosomal and telomere analysis in Fig. 2. We apologize to the members of the scientific community whose work could not be cited owing to space limitations. Grant support for our work was provided by National Institutes of Health grants RO1CA84628 and U01 CA84313, US Department of Defense grant W81XWH-08-1-0133, and the Ellison Medical Foundation. R.A.D. is an American Cancer Society Research Professor and is supported by the Robert A. and Renée E. Belfer Foundation Institute for Innovative Cancer Science. E.S. was supported by the Deutsche Forschungsgemeinschaft.
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Reprints and permissions information is available at http://www.nature.com/reprints. The authors declare no competing financial interests. Correspondence should be addressed to the R.A.D. (ron_depinho@dfci.harvard.edu).
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Sahin, E., DePinho, R. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010). https://doi.org/10.1038/nature08982
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DOI: https://doi.org/10.1038/nature08982
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