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Updated: Jun 2, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Premature aging with impaired oxidative stress defense in mice lacking TR4
Yi-Fen Lee1, Su Liu, Ning-Chun Liu
1George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Orthopaedics, University of Rochester Medical Center, Rochester, New York 14620, USA. chang@urmc.rochester.edu
Abstract:
Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
Insights
Mice lacking the TR4 nuclear receptor show genome instability and poor oxidative stress defense, leading to premature aging. Restoring TR4 or using antioxidants like NAC mitigates DNA damage and slows aging in these mice.
Area of Science:
- Molecular Biology
- Genetics
- Aging Research
Background:
- The TR4 nuclear receptor is a known regulator of reproduction, development, and metabolism.
- Genome instability and oxidative stress are implicated in aging processes.
Purpose of the Study:
- To investigate the role of TR4 in genome stability, oxidative stress defense, and aging.
- To explore the cellular mechanisms underlying premature aging in TR4-deficient mice.
Main Methods:
- Generation and analysis of TR4-deficient (TR4(-/-)) mice.
- In vitro studies using TR4(-/-) mouse embryonic fibroblasts (MEFs).
- Assessment of DNA damage, oxidative stress, cellular growth, and gene expression profiles (qPCR array).
Main Results:
- TR4(-/-) mice exhibited genome instability, defective oxidative stress defense, and premature aging phenotypes.
- TR4(-/-) MEFs showed rapid growth arrest and reduced resistance to oxidative stress and DNA damage.
- Restoring TR4 or treating with N-acetyl-l-cysteine (NAC) reduced DNA damage and growth arrest in TR4(-/-) MEFs.
- Gene expression analysis revealed altered DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs.
Conclusions:
- TR4 plays a critical role in maintaining genome integrity and oxidative stress defense.
- Oxidative DNA damage resulting from compromised genome integrity or increased oxidative stress contributes to premature aging in TR4(-/-) mice.
- TR4 mediates the crucial interplay between oxidative stress defense and the aging process.
