Impaired Genome Maintenance Suppresses the Growth Hormone–Insulin-Like Growth Factor 1 Axis in Mice with Cockayne Syndrome

Abstract

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.

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

“…The second related paper, by van der Pluijm et al (van der Pluijm et al, 2007), focused on a different NER-deficient model, the Csb m/m /Xpa-/-mouse. In humans, defects in the Cockayne syndrome (CS) A or B genes result in a transcriptional coupled NER defect, and these individuals exhibit growth failure, progressive neurological defects, along with kyphosis, osteoporosis, and a dramatically reduced mean life span of 12.5 years (Cleaver, 2005;Nance and Berry, 1992).…”

“…In humans, defects in the Cockayne syndrome (CS) A or B genes result in a transcriptional coupled NER defect, and these individuals exhibit growth failure, progressive neurological defects, along with kyphosis, osteoporosis, and a dramatically reduced mean life span of 12.5 years (Cleaver, 2005;Nance and Berry, 1992). Mice mutant for CS-B show some phenotypes of the human syndrome (van der Horst et al, 1997), but when crossed to NER-deficient Xpa-/-mice, the NER defect is complete and defective phenotypes are exacerbated, resembling those of the Ercc1-/-mice (van der Pluijm et al, 2007). The Csb m/m /Xpa-/-mice were growth retarded, exhibited multiple tissue defects, and had progeroid phenotypes, ultimately dying by 22 days of age.…”

“…Thus, the obvious question is whether increased p53 levels in the Ercc1-/-and Csb mm /Xpa-/-mice have a causative role in their progeroid phenotypes (Laposa, Huang, and Cleaver, 2007;McWhir et al, 1993). Van der Pluijm et al (van der Pluijm et al, 2007) briefly indicate that introduction of p53 nullizygosity into the Csb mm /Xpa-/-mice failed to rescue any of the detrimental phenotypes. It could be argued that the p53 pathway is only one of the DNA damage response pathways activated by the NER deficiency and while perhaps contributing to the aging phenotypes, its inactivation is not sufficient for phenotype rescue.…”

“…The underlying assumption of the models proposed by Niedernhofer et al (Niedernhofer et al, 2006) and van der Pluijm et al (van der Pluijm et al, 2007) is that the suppression of IGF-1 signaling by DNA damage is generally protective against the ravages produced by such damage (van de Ven et al, 2007). Ultimately, however, despite this protective effect, NER-deficient cells incur too much damage and cells are lost at too high a rate to prevent loss of tissue homeostasis.…”

“…To further complicate this picture, two seminal papers by Niedernhofer et al (Niedernhofer et al, 2006) and van der Pluijm et al (van der Pluijm et al, 2007) describe nucleotide excision repair (NER) deficient mice with progeroid phenotypes and very short life spans. Interestingly, both repair-deficient models exhibited greatly reduced serum IGF-1.…”