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, Jan H.J. Hoeijmakers

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

552 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1038-1043
Aantal pagina's6
TijdschriftNature
Volume444
Nummer van het tijdschrift7122
DOI's
StatusGepubliceerd - 21 dec. 2006
Extern gepubliceerdJa

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