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Hepatic response to oxidative injury in long-lived Ames dwarf mice
Liou Y Sun1, Alex F Bokov, Arlan Richardson
1Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-0940, USA.
Abstract:
Multiple stress resistance pathways were evaluated in the liver of Ames dwarf mice before and after exposure to the oxidative toxin diquat, seeking clues to the exceptional longevity conferred by this mutation. Before diquat treatment, Ames dwarf mice, compared with nonmutant littermate controls, had 2- to 6-fold higher levels of expression of mRNAs for immediate early genes and 2- to 5-fold higher levels of mRNAs for genes dependent on the transcription factor Nrf2. Diquat led to a 2-fold increase in phosphorylation of the stress kinase ERK in control (but not Ames dwarf) mice and to a 50% increase in phosphorylation of the kinase JNK2 in Ames dwarf (but not control) mice. Diquat induction of Nrf2 protein was higher in dwarf mice than in controls. Of 6 Nrf2-responsive genes evaluated, 4 (HMOX, NQO-1, MT-1, and MT-2) remained 2- to 10-fold lower in control than in dwarf liver after diquat, and the other 2 (GCLM and TXNRD) reached levels already seen in dwarf liver at baseline. Thus, livers of Ames dwarf mice differ systematically from controls in multiple stress resistance pathways before and after exposure to diquat, suggesting mechanisms for stress resistance and extended longevity in Ames dwarf mice.
Insights
Ames dwarf mice exhibit enhanced stress resistance pathways, including higher gene expression and improved responses to oxidative toxins. These findings suggest mechanisms contributing to their exceptional longevity.
Area of Science:
- Cellular Biology
- Genetics
- Toxicology
Background:
- Ames dwarf mice exhibit extended longevity.
- Understanding the molecular basis of longevity is crucial for human healthspan research.
- Oxidative stress is implicated in aging and age-related diseases.
Purpose of the Study:
- To investigate stress resistance pathways in Ames dwarf mice.
- To determine the role of these pathways in the longevity of Ames dwarf mice.
- To examine the response of Ames dwarf mice to oxidative toxin diquat.
Main Methods:
- Gene expression analysis (mRNA levels) in liver tissue.
- Western blotting for protein phosphorylation (ERK, JNK2).
- Evaluation of Nrf2-responsive genes after diquat exposure.
Main Results:
- Ames dwarf mice showed higher baseline mRNA levels for immediate early genes and Nrf2-dependent genes.
- Diquat induced differential stress kinase activation (ERK in controls, JNK2 in dwarfs).
- Diquat-induced Nrf2 protein levels were higher in dwarf mice, with key Nrf2-responsive genes showing altered expression patterns.
Conclusions:
- Ames dwarf mice possess distinct, robust stress resistance pathways.
- These pathways contribute to their resistance to oxidative stress.
- The findings provide insights into the mechanisms underlying Ames dwarf mouse longevity.
