Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.
Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) 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 Xpd(TTD) mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD) 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 Xpd(TTD) 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.
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Jung Yoon
JY
Park
Mi-Ook
MO
Cho
Shanique
S
Leonard
Brent
B
Calder
I Saira
IS
Mian
Woo Ho
WH
Kim
Susan
S
Wijnhoven
Harry
H
van Steeg
James
J
Mitchell
Gijsbertus T J
GT
van der Horst
Jan
J
Hoeijmakers
Pinchas
P
Cohen
Jan
J
Vijg
Yousin
Y
Suh
D019588:Aging, Premature / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004734:Energy Metabolism; D005260:Female; D006706:Homeostasis; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D051379:Mice; D014158:Transcription, Genetic; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D007334:Insulin-Like Growth Factor I; D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse