Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice

Abstract

Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing XpdTTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the XpdTTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the XpdTTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

Clinical significance of high focal adhesion kinase gene copy number and overexpression in invasive breast cancer

“…All tissues obtained from patients were routinely fixed in 10% buffered formalin and embedded in paraffin blocks. Tissue arrays were used for high throughput study as previously described [23][24][25][26]. After screening the slides of each case, we selected a paraffin block that was well-fixed and contained a representative section of tumor.…”

Cockayne syndrome pathogenesis: Lessons from mouse models

“…Xpd TTD mice are born at Mendelian frequency without obvious abnormalities, show mildly reduced weight gain during early post-natal life, and a somewhat reduced mean life span (Andressoo et al, 2006a;de Boer et al, 1998a;van de Ven et al, 2012). Xpd TTD mice are also well known as a model for accelerated aging of a number of tissues, in particular skin and bone (Andressoo et al, 2006a;de Boer et al, 2002;Nicolaije et al, 2012;Park et al, 2008;van de Ven et al, 2012;Wijnhoven et al, 2005). In addition, Xpd TTD mice were reported to show subtle abnormalities in myelin development .…”

COX2 overexpression is a prognostic marker for Stage III breast cancer

“…Tissues obtained from patients were routinely fixed in 10% buffered formalin and embedded in paraffin blocks. Tissue arrays were used for high-throughput study, as described previously [17][18][19][20]. After screening the slides from each case, we selected a paraffin block that was well-fixed and contained a representative section of tumor.…”