Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging XpdTTD mice

Jung Yoon Park, Mi Ook Cho, Shanique Leonard, Brent Calder, I. Saira Mian, Woo Ho Kim, Susan Wijnhoven, Harry van Steeg, James Mitchell, Gijsbertus T.J. van der Horst, Jan Hoeijmakers, Pinchas Cohen, Jan Vijg, Yousin Suh

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22 Scopus citations

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 rduced 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.

Original languageEnglish (US)
Article numbere2346
JournalPloS one
Volume3
Issue number6
DOIs
StatePublished - Jun 11 2008

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Park, J. Y., Cho, M. O., Leonard, S., Calder, B., Mian, I. S., Kim, W. H., Wijnhoven, S., van Steeg, H., Mitchell, J., van der Horst, G. T. J., Hoeijmakers, J., Cohen, P., Vijg, J., & Suh, Y. (2008). Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging XpdTTD mice. PloS one, 3(6), [e2346]. https://doi.org/10.1371/journal.pone.0002346