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

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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.

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Figure 1: Molecular characterization of progeroid patient ‘XFE’.
Figure 2: Progeroid characteristics of Ercc1 -/- mice.
Figure 3: Confirmation of microarray expression data by qRT-PCR and physiologic endpoints.
Figure 4: Growth-hormone–IGF1 suppression is a normal physiological response to DNA damage.
Figure 5: Comparison of the physiological changes due to DNA repair defects and ageing.

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Acknowledgements

This research was supported by the National Institute of Aging Program, the Dutch Cancer Society, the Dutch Science Foundation (NWO) through the foundation of the Research Institute Diseases of the Elderly, as well as grants from SenterNovem IOP-Genomics, the NIH, the NIA Program Project, the NIEHS center, the EC, and Human Frontier Science Program. J.H.J.H. is chief scientific officer of DNage. L.J.N. was supported by a postdoctoral fellowship from the American Cancer Society and subsequently by the NCI and The Ellison Medical Foundation, along with A.R.R. and A.A. We thank P. Nair, F. J. Calderon, R. B. Calder and D. Muñoz-Medellin of the Sam and Ann Barshop Center, University of Texas Health Science Center, for their contributions to the preliminary microarray analysis.

Author Contributions Human cells characterized by L.J.N., A.R., E.A., H.O., A.A., A.F.T., W.V. and N.G.J.J. Experimental analysis of mice by L.J.N., A.S.L., A.R.R. and R.O. Microarray analysis by L.J.N., G.A.G., G.T.J. v. d. H. and J.V. Radiography by W. v. L. Clinical services by P.M. and W.J.K. Manuscript prepared by L.J.N., G.A.G and J.H.J.H.

The expression data for Ercc1-/- mice are deposited in ArrayExpress 〈http://www.ebi.ac.uk/arrayexpress/〉, a public repository for microarray data, which stores Minimum Information for Microarray Experiments (MIAME)-compliant data in accordance with Microarray Gene Expression Data (MGED) recommendations. The accession number is E-MEXP-834. The accession number for the expression data on the aged mice is E-MEXP-839 (ref. 28).

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Correspondence to Jan H. J. Hoeijmakers.

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Supplementary information

This file contains Supplementary Notes, Supplementary Methods, Supplementary Figures 1-5 with legends and Supplementary Tables 1-8.

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Niedernhofer, L., Garinis, G., Raams, A. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006) doi:10.1038/nature05456

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