ArticleFree radical biology & medicine2015
Age-related loss of hepatic Nrf2 protein homeostasis: Potential role for heightened expression of miR-146a.
Article in Free radical biology & medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
- Integrating Structural Characterization, Network Pharmacology, and Experimental Validation Reveals the Anti-Liver Aging Mechanism of Acorus tatarinowii Polysaccharides.Chemistry & biodiversity · 2026Article
- Crosstalk Between Nrf2 and Metabolic Pathways: Redox Regulation, Glutaminolysis, and Cellular Proliferation.Cell biochemistry and biophysics · 2026Review
- miR-146a Regulates Neuroinflammation and Immune Cell Function in Neurodegenerative Diseases.Current medical science · 2025Review
- Upregulation of the Antioxidant Response-Related microRNAs miR-146a-5p and miR-21-5p in Gestational Diabetes: An Analysis of Matched Samples of Extracellular Vesicles and PBMCs.International journal of molecular sciences · 2025Article
- Oxidative Stress, MicroRNAs, and Long Non-Coding RNAs in Osteoarthritis Pathogenesis: Cross-Talk and Molecular Mechanisms Involved.International journal of molecular sciences · 2025Review
- Article
- Cytoprotection against Cadmium by Nrf2-Activating Dietary Phytochemicals.HSOA journal of alternative, complementary & integrative medicine · 2024Article
- Effect of Nrf2 loss on senescence and cognition of tau-based P301S mice.GeroScience · 2023Article
- MicroRNAs in Age-Related Proteostasis and Stress Responses.Non-coding RNA · 2023Review
- The Complex Genetic and Epigenetic Regulation of the Nrf2 Pathways: A Review.Antioxidants (Basel, Switzerland) · 2023Review
- Insulin and aging - a disappointing relationship.Frontiers in endocrinology · 2023Review
- Effects of trehalose on NFE2L2, catalase, and superoxide dismutase in the kidney of aged rats.Molecular biology research communications · 2022Article
- MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence.Antioxidants (Basel, Switzerland) · 2022Review
- Effects of the Phytochemical Combination PB123 on Nrf2 Activation, Gene Expression, and the Cholesterol Pathway in HepG2 Cells.OBM integrative and complimentary medicine · 2022Article
- Dietary supplementation with sulforaphane ameliorates skin aging through activation of the Keap1-Nrf2 pathway.The Journal of nutritional biochemistry · 2021Article
- The KEAP1-NRF2 System in Healthy Aging and Longevity.Antioxidants (Basel, Switzerland) · 2021Review
- Nrf2 activator PB125® as a carnosic acid-based therapeutic agent against respiratory viral diseases, including COVID-19.Free radical biology & medicine · 2021Review
- Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis.Cell death & disease · 2021Article
- Protective effects of bovine milk exosomes against oxidative stress in IEC-6 cells.European journal of nutrition · 2021Article
- Phytochemical Combination PB125 Activates the Nrf2 Pathway and Induces Cellular Protection against Oxidative Injury.Antioxidants (Basel, Switzerland) · 2019Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Nrf2 regulates the expression of numerous anti-oxidant, anti-inflammatory, and metabolic genes. We observed that, paradoxically, Nrf2 protein levels decline in the livers of aged rats despite the inflammatory environment evident in that organ. To examine the cause(s) of this loss, we investigated the age-related changes in Nrf2 protein homeostasis and activation in cultured hepatocytes from young (4-6 months) and old (24-28 months) Fischer 344 rats. While no age-dependent change in Nrf2 mRNA levels was observed (p>0.05), Nrf2 protein content, and the basal and anetholetrithione (A3T)-induced expression of Nrf2-dependent genes were attenuated with age. Conversely, overexpression of Nrf2 in cells from old animals reinstated gene induction. Treatment with A3T, along with bortezomib to inhibit degradation of existing protein, caused Nrf2 to accumulate significantly in cells from young animals (p<0.05), but not old, indicating a lack of new Nrf2 synthesis. We hypothesized that the loss of Nrf2 protein synthesis with age may partly stem from an age-related increase in microRNA inhibition of Nrf2 translation. Microarray analysis revealed that six microRNAs significantly increase >2-fold with age (p<0.05). One of these, miRNA-146a, is predicted to bind Nrf2 mRNA. Transfection of hepatocytes from young rats with a miRNA-146a mimic caused a 55% attenuation of Nrf2 translation that paralleled the age-related loss of Nrf2. Overall, these results provide novel insights for the age-related decline in Nrf2 and identify new targets to maintain Nrf2-dependent detoxification with age.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.