Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csbm/m/Xpa−/− mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csbm/m/Xpa−/− mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csbm/m/Xpa−/− and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair–deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.
Studies in mice defective in two DNA repair pathways (global NER and TCR; an animal model for Cockayne syndrome) highlight a link between aging, a failure to repair DNA lesions, and metabolic alterations.
Normal metabolism routinely produces reactive oxygen species that damage DNA and other cellular components and is thought to contribute to the ageing process. Although DNA damage is typically kept in check by a variety of enzymes, several premature ageing disorders result from failure to remove damage from active genes. Patients with Cockayne syndrome (CS), a genetic mutation affecting one class of DNA repair enzymes, display severe growth retardation, neurological symptoms, and signs of premature ageing followed by an early death. Whereas mouse models for CS exhibit relatively mild deficits, we show that concomitant inactivation of a second DNA repair gene elicits severe CS pathology and ageing. Moreover, a few days after birth, these mice undergo systemic suppression of genes controlling growth, an unexpected decrease in oxidative metabolism, and an increased antioxidant response. Similar physiological changes are also triggered in normal mice by chronic exposure to DNA-damaging oxidative stress. From these findings, we conclude that DNA damage triggers a response aimed at limiting oxidative DNA damage levels (and associated tissue degeneration) to extend lifespan and promote healthy ageing. Better understanding of the ageing process will help to delineate intervention strategies to combat age-associated pathology.