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 mutantspecific 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. Thesemore »
- Authors:
-
- Albert Einstein College of Medicine, Bronx, NY (United States)
- University of Texas at San Antonio, TX (United States)
- Buck Institute for Age Research, Novato, CA (United States)
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Seoul National University (Korea, Republic of)
- National Institute of Public Health and the Environment, Bilthoven (Netherlands)
- Erasmus University, Rotterdam (Netherlands)
- University of California, Los Angeles, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- OSTI Identifier:
- 1627352
- Grant/Contract Number:
- AC02-05CH11231; RO1 AG024391; RO3 AG023292; PO1 AG17242; RO1AG20438; UO1ES11044
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 3; Journal Issue: 6; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; apoptosis; mouse models; aging and cancer; microarrays; aging; lipid metabolism; gene expression; gene ontologies
Citation Formats
Park, Jung Yoon, Cho, Mi-Ook, Leonard, Shanique, Calder, Brent, Mian, I. Saira, Kim, Woo Ho, Wijnhoven, Susan, van Steeg, Harry, Mitchell, James, van der Horst, Gijsbertus T. J., Hoeijmakers, Jan, Cohen, Pinchas, Vijg, Jan, and Suh, Yousin. Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice. United States: N. p., 2008.
Web. doi:10.1371/journal.pone.0002346.
Park, Jung Yoon, Cho, Mi-Ook, Leonard, Shanique, Calder, Brent, Mian, I. Saira, Kim, Woo Ho, Wijnhoven, Susan, van Steeg, Harry, Mitchell, James, van der Horst, Gijsbertus T. J., Hoeijmakers, Jan, Cohen, Pinchas, Vijg, Jan, & Suh, Yousin. Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice. United States. https://doi.org/10.1371/journal.pone.0002346
Park, Jung Yoon, Cho, Mi-Ook, Leonard, Shanique, Calder, Brent, Mian, I. Saira, Kim, Woo Ho, Wijnhoven, Susan, van Steeg, Harry, Mitchell, James, van der Horst, Gijsbertus T. J., Hoeijmakers, Jan, Cohen, Pinchas, Vijg, Jan, and Suh, Yousin. Wed .
"Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice". United States. https://doi.org/10.1371/journal.pone.0002346. https://www.osti.gov/servlets/purl/1627352.
@article{osti_1627352,
title = {Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice},
author = {Park, Jung Yoon and Cho, Mi-Ook and Leonard, Shanique and Calder, Brent and Mian, I. Saira and Kim, Woo Ho and Wijnhoven, Susan and van Steeg, Harry and Mitchell, James and van der Horst, Gijsbertus T. J. and Hoeijmakers, Jan and Cohen, Pinchas and Vijg, Jan and Suh, Yousin},
abstractNote = {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 mutantspecific 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.},
doi = {10.1371/journal.pone.0002346},
journal = {PLoS ONE},
number = 6,
volume = 3,
place = {United States},
year = {Wed Jun 11 00:00:00 EDT 2008},
month = {Wed Jun 11 00:00:00 EDT 2008}
}
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