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

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