A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis

Laura J. Niedernhofer, George A. Garinis, Anja Raams, Astrid S. Lalai, Andria Rasile Robinson, Esther Appeldoorn, Hanny Odijk, Roos Oostendorp, Anwaar Ahmad, Wibeke van Leeuwen, Arjan F. Theil, Wim Vermeulen, Gijsbertus T. J. van der Horst, Peter Meinecke, Wim J. Kleijer, Jan Vijg, Nicolaas G. J. Jaspers and Jan H. J. Hoeijmakers ()
Additional contact information
Laura J. Niedernhofer: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
George A. Garinis: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Anja Raams: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Astrid S. Lalai: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Andria Rasile Robinson: University of Pittsburgh School of Medicine
Esther Appeldoorn: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Hanny Odijk: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Roos Oostendorp: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Anwaar Ahmad: University of Pittsburgh School of Medicine
Wibeke van Leeuwen: Department of Experimental Radiology
Arjan F. Theil: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Wim Vermeulen: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Gijsbertus T. J. van der Horst: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Peter Meinecke: Abteilung für Medizinische Genetik, Altonaer KinderKrankenhaus
Wim J. Kleijer: Erasmus Medical Center
Jan Vijg: The Buck Institute for Age Research
Nicolaas G. J. Jaspers: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
Jan H. J. Hoeijmakers: Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics

Nature, 2006, vol. 444, issue 7122, 1038-1043

Abstract: Abstract XPF–ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF–ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Date: 2006
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DOI: 10.1038/nature05456

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