Nrf2 signaling is impaired in the aging RPE given an oxidative insult
Open accessAbstract
Age-related macular degeneration (AMD) represents the leading cause of blindness in the elderly, yet no definitive therapy exists for early, dry disease. Several lines of evidence have implicated oxidative stress-induced damage to the retinal pigment epithelium (RPE) in the pathogenesis of AMD, suggesting that the aging RPE may exhibit increased susceptibility to cell damage induced by exogenous stressors. The transcription factor Nrf2 serves as the master regulator of a highly coordinated antioxidant response in virtually all cell types. We compared Nrf2 signaling in the RPE of young (2 months) and old (15 months) mice under unstressed and stressed (sodium iodate) conditions. The aging RPE expressed higher levels of the Nrf2 target genes NQO1, GCLM, and HO1 compared with the RPE of younger mice under unstressed conditions, suggesting an age-related increase in basal oxidative stress. Moreover, the RPE of older mice demonstrated impaired induction of the protective Nrf2 pathway following oxidative stress induced with sodium iodate. The RPE of old mice exposed to sodium iodate also exhibited higher levels of superoxide anion and malondialdehyde than young mice, suggesting inadequate protection against oxidative damage. Induction of Nrf2 signaling in response to sodium iodate was partially restored in the RPE of aging mice with genetic rescue, using conditional knockdown of the Nrf2 negative regulator Keap1 (Tam-Cre; Keap1loxP) compared to Keap1loxP mice. These data indicate that the aging RPE is vulnerable to oxidative damage due to impaired Nrf2 signaling, and that Nrf2 signaling is a promising target for novel pharmacologic or genetic therapeutic strategies.
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Nrf2 signaling decreases with age in a variety of model organisms including flies, mice, non-human primates, and humans.
“Nrf2 signaling has been found to decrease with age [207] in a variety of model organisms including flies [208], mice [209], non-human primates [210,211], and humans [207,212,213,214].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [209]
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“Because p62 regulates multiple functions including autophagy, proteasomal clearance, and the antioxidant stress response via NRF2/KEAP1 signaling, phase separation of p62 could compromise many pathways implicated in AMD (62, 72, 73).”
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“In aging RPE, induction of NRF2 signaling is compromised with oxidative stress (Sachdeva et al., 2014).”
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“Oxidative stress has also been found to adversely affect Nrf2 signaling in RPE cells with AMD [62,63].”
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“Previous research showed that aging RPE cell are susceptible to oxidative damage due to Nrf2 signaling.(46) Another study found that BPA could increase overall oxidative stress and engender a decrease in malondialdehyde and glutathione in chicken embryo brain tissue.”
BackgroundKoh, A. E.-H., Alsaeedi, H. A., Rashid, M. B. A., Lam, C., Harun, M. H. N., Saleh, M. F. B. M., Luu, C. D., Kumar, S. S., Ng, M. H., Isa, H. M., et al. (2019) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2019.111514 · Cited by 49 · see citing works
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Regulated cell death pathways in the sodium iodate model: Insights and implications for AMD
Upadhyay, M., & Bonilha, V. L. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109728 · Cited by 48 · see citing works
Nrf2 in aging – Focus on the cardiovascular system
Klóska, D., Kopacz, A., Piechota-Polańczyk, A., Nowak, W. N., Dulak, J., Józkowicz, A., & Grochot‐Przeczek, A. (2018) · Vascular Pharmacology · doi:10.1016/j.vph.2018.08.009 · Cited by 47 · see citing works
Diéguez, H. H., Fleitas, M. F. G., Aranda, M. L., Calanni, J. S., Sarmiento, M. I. K., Chianelli, M. S., Alaimo, A., Sande, P. H., Romeo, H. E., Rosenstein, R. E., et al. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12643 · Cited by 46 · see citing works
Berkowitz, B. A., Podolsky, R. H., Lenning, J. C., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Khorassani, F. S., & Roberts, R. (2017) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.17-21850 · Cited by 45 · see citing works
“Low doses of sodium iodate (SI) are reported to produce more outer retinal atrophy on histologic examination in B6 mice than in S6 mice.(2,23,31,32) Thus, we hypothesized that before overt atrophy, SI-treated B6 mice experience more outer retinal oxidative stress than SI-treated S6 mice.”
BackgroundTrakkides, T.-O., Schäfer, N., Reichenthaler, M., Kühn, K., Brandwijk, R. J. M. G. E., Toonen, E. J. M., Urban, F., Wegener, J., Enzmann, V., & Pauly, D. (2019) · Antioxidants · doi:10.3390/antiox8110548 · Cited by 45 · see citing works
“reactive oxygen species are required to maintain physiological functions [3], but the combination of visible light exposure, elevated metabolic activity, the accumulation of oxidized lipoproteins, and decreased antioxidant functions during aging make the retinal tissue vulnerable to oxidative stress [4,5].”
BackgroundLi, Y., Cheng, Z., Wang, K., Zhu, X., Ali, Y., Shu, W., Bao, X., Zhu, L., Fan, X., Murray, M. T., et al. (2021) · Experimental Eye Research · doi:10.1016/j.exer.2021.108586 · Cited by 43 · see citing works
Ildefonso, C. J., Jaime, H., Brown, E. E., Iwata, R. L., Ahmed, C. M. I., Massengill, M. T., Biswal, M. R., Boye, S. L., Hauswirth, W. W., Ash, J. D., et al. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17703 · Cited by 42 · see citing works
“Although this peptide holds potential for therapy, it would require repeated administration to treat chronic inflammatory disease, such as AMD.”
BackgroundInfluentialEpigenetic Mechanisms of the Aging Human Retina
Pennington, K. L., & DeAngelis, M. M. (2015) · Journal of Experimental Neuroscience · doi:10.4137/jen.s25513 · Cited by 41 · see citing works
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“It has been reported that antioxidants protect oxidative stress-induced RPE cells by activating Nrf2 signaling (19).”
Huang, S.-Y., Chang, S.-F., Chau, S.-F., & Chiu, S. (2019) · Biomolecules · doi:10.3390/biom9080380 · Cited by 41 · see citing works
“Recent studies also indicate that antioxidants work against oxidative stresses in RPE cells by activating Nrf2 signaling [11,12].”
BackgroundOxidative stress and mitochondrial transfer: A new dimension towards ocular diseases
Subramaniam, M. D., Iyer, M., Nair, A. P., Venkatesan, D., Mathavan, S., Eruppakotte, N., Kizhakkillach, S., Chandran, M. K., Roy, A., Gopalakrishnan, A. V., et al. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.11.020 · Cited by 41 · see citing works
4-Acetoxyphenol Prevents RPE Oxidative Stress–Induced Necrosis by Functioning as an NRF2 Stabilizer
Hanus, J., Kolkin, A., Chimienti, J., Botsay, S., & Wang, S. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-16401 · Cited by 40 · see citing works
Garcia, T. Y., Gutierrez, M. A., Reynolds, J. C., & Lamba, D. A. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17251 · Cited by 40 · see citing works
Kim, M. H., Kwon, S. Y., Woo, S.-Y., Seo, W. D., & Kim, D. Y. (2021) · Molecules · doi:10.3390/molecules26020313 · Cited by 40 · see citing works
Diéguez, H. H., Romeo, H. E., Alaimo, A., Fleitas, M. F. G., Aranda, M. L., Rosenstein, R. E., & Dorfman, D. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.11.035 · Cited by 38 · see citing works
Oxidative stress and antioxidants in the trabecular meshwork
Wang, M., & Zheng, Y. (2019) · PeerJ · doi:10.7717/peerj.8121 · Cited by 38 · see citing works
Alzheimer's Disease and NQO1: Is there a Link?
Chhetri, J., King, A. E., & Gueven, N. (2017) · Current Alzheimer Research · doi:10.2174/1567205014666170203095802 · Cited by 37 · see citing works
Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity
Casares, L., Unciti-Broceta, J. D., Prados, M. E., Caprioglio, D., Mattoteia, D., Higgins, M., Appendino, G., Dinkova‐Kostova, A. T., Muñóz, E., & de la Vega, L. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101689 · Cited by 37 · see citing works
“It is noteworthy that with aging, NRF2 signaling is 367 impaired [54] [55] [56].”
BackgroundCatanzaro, M., Lanni, C., Basagni, F., Rosini, M., Govoni, S. M., & Amadio, M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00844 · Cited by 36 · see citing works
“The most comprehensive transcription system used by RPE to neutralize oxidative stress and maintain cellular homeostasis is the Keap1-Nrf2-ARE pathway (Sachdeva et al., 2014; Lambros and Plafker, 2016).”
BackgroundHwang, N., Kwon, M., Woo, J. M., & Chung, S. W. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236028 · Cited by 35 · see citing works
“In general, oxidative stress is a well-known stimulus for RPE dysfunction in aging and the development of AMD [6,11,12].”
BackgroundAge-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms
Bak, M., Sørensen, T. L., Flachs, E. M., Zwisler, A., Juel, K., Frederiksen, H., & Hasselbalch, H. C. (2017) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2017.2011 · Cited by 34 · see citing works
Zeng, J., Liao, S., Liang, Z., Li, C., Luo, Y., Wang, K., Zhang, D., Lan, L., Hu, S., Li, W., et al. (2023) · European journal of medical research · doi:10.1186/s40001-023-01190-8 · Cited by 33 · see citing works
Rowan, S., Jiang, S., Chang, M., Volkin, J., Cassalman, C., Smith, K., Streeter, M. D., Spiegel, D. A., Neto, C. A. M., Rabbani, N., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.02.010 · Cited by 33 · see citing works
“Therefore, pathways that can exploit Nrf2 or its functionality represent promising interventional targets to treat disease, particularly agerelated diseases, where function of Nrf2 diminishes with age and oxidative stresses increase (21, 56).”
BackgroundSuárez‐Barrio, C., del Olmo‐Aguado, S., García-Pérez, E., de la Fuente, M., Muruzábal, F., Anitua, E., Baamonde-Arbaiza, B., Fernández-Vega-Cueto, L., Fernández-Vega-Cueto, L., & Merayo-Llovés, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031021 · Cited by 32 · see citing works
“The expression of antioxidant genes such as Nrf2, HO-1, GCL, and NQO1 was increased in the presence of blue light.”
BackgroundInfluentialParaoan, L., Sharif, U., Carlsson, E., Supharattanasitthi, W., Mahmud, N. M., Kamalden, T. A., Hiscott, P. S., Jackson, M. J., & Grierson, I. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100859 · Cited by 31 · see citing works
Abokyi, S., Shan, S. W., To, C. H., Chan, H. H., & Tse, D. Y. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5296341 · Cited by 32 · see citing works
“Studies have reported that the major risk factors of AMD, including aging and cigarette smoking, promote oxidative damage to RPE cells by inhibition of NRF2 antioxidant defense [11, 12].”
BackgroundTakayama, K., Kaneko, H., Kataoka, K., Kimoto, R., Hwang, S.-J., Ye, F., Nagasaka, Y., Tsunekawa, T., Matsuura, T., Nonobe, N., et al. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8694641 · Cited by 31 · see citing works
“Nrf2 also serves as the master regulator of a highly coordinated antioxidant response in RPE cells [25].”
BackgroundGospodaryov, D. V., Strilbytska, O., Semaniuk, U., Perkhulyn, N. V., Rovenko, B., Yurkevych, I., Barata, A. G., Dick, T., Lushchak, O., & Jacobs, H. (2019) · Biogerontology (Dordrecht) · doi:10.1007/s10522-019-09849-8 · Cited by 24 · see citing works
Markitantova, Y. V., & Simirskii, V. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310776 · Cited by 29 · see citing works
Optimizing the sodium iodate model: Effects of dose, gender, and age
Anderson, B. D., Lee, T. T., Bell, B. A., Wang, T., & Dunaief, J. L. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109772 · Cited by 29 · see citing works
Wang, Y., Qian, M., Qu, Y., Yang, N., Mu, B., Liu, K., Yang, J., Zhou, Y., Ni, C., Zhong, J., et al. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00122 · Cited by 28 · see citing works
Byrne, A. M., Ruiz‐Lopez, A. M., Roche, S. L., Moloney, J. N., Wyse‐Jackson, A. C., & Cotter, T. G. (2016) · Redox Biology · doi:10.1016/j.redox.2016.10.002 · Cited by 27 · see citing works
“It has been shown that the aging RPE exhibits dysregulated Nrf2 signaling, leading to impaired induction of antioxidant genes [68], while knockout of nrf2 in otherwise healthy mice increases the susceptibility of the outer retina to age-related degeneration [69].”
BackgroundCheng, J., Liang, J., & Qi, J. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4543 · Cited by 27 · see citing works
“Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a central regulator of cellular oxidation reactions and serves a key role in cell defense mechanisms against oxidative stress (25-29).”
Zhou, J., Chen, F., Yan, A.-M., & Xia, X. (2020) · Bioscience Reports · doi:10.1042/bsr20194347 · Cited by 27 · see citing works
Rappaport, A. N., Jacob, E., Sharma, V. K., Inberg, S., Elkobi, A., Ounallah-Saad, H., Pasmanik‐Chor, M., Edry, E., & Rosenblum, K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1170-15.2015 · Cited by 27 · see citing works
“After a preliminary screening for differential mRNA expression in the IC of animals that learned negative or positive tastes, we focused our study on quinone reductase 2 (QR2), one of two primary quinone reductases found in mammals: QR1 and QR2 (or NQO1 and NQO2, respectively).”
BackgroundChen, W., Ye, Y., Wu, Z., Lin, J., Wang, Y., Ding, Q., Yang, X., Yang, W., Lin, B., & Lin, B. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/4053276 · Cited by 26 · see citing works
de Oliveira, M. R., Brasil, F. B., & Fürstenau, C. R. (2018) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1027-0 · Cited by 26 · see citing works
“Disruption in the Nrf2mediated signaling is associated with generalized cell dysfunction, as observed experimentally and in human diseases (Jin et al. 2013; Sachdeva et al. 2014).”
Cui, R., Tian, L., Lu, D., Li, H., & Cui, J. (2019) · Ophthalmic Research · doi:10.1159/000504891 · Cited by 26 · see citing works
Sorenson, C. M., Song, Y., Zaitoun, I. S., Wang, S., Hanna, B. A., Darjatmoko, S. R., Gürel, Z., Fisk, D. L., McDowell, C. M., McAdams, R. M., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.737426 · Cited by 25 · see citing works
“Since AMD pathogenesis and CNV is significantly impacted by aging (Chen et al., 2010; Sachdeva et al., 2014; Edwards et al., 2016; Ma and Wong, 2016), we determined whether the Frontiers in Cell and Developmental Biology | www.frontiersin.org 9 October 2021 | Volume 9 | Article 737426 FIGURE 6 |…”
BackgroundShilovsky, G. A. (2022) · Biochemistry (Moscow) · doi:10.1134/s0006297922010060 · Cited by 25 · see citing works
“Activation of this pathway may be a highly promising approach for developing novel pharma cological or genetic therapeutic strategies [28].”
BackgroundInfluentialAn inducible form of Nrf2 confers enhanced protection against acute oxidative stresses in RPE cells
Vu, K. T., & Hulleman, J. D. (2017) · Experimental Eye Research · doi:10.1016/j.exer.2017.08.001 · Cited by 24 · see citing works
“It is generally accepted that the ability of many cells within the body (including retinal cells) to mount an effective antioxidant response declines with age (Bruns et al., 2015; Sachdeva et al., 2014; Suh et al., 2004).”
Macchioni, L., Chiasserini, D., Mezzasoma, L., Davidescu, M., Orvietani, P. L., Fettucciari, K., Salviati, L., Cellini, B., & Bellezza, I. (2020) · Antioxidants · doi:10.3390/antiox10010025 · Cited by 26 · see citing works
“Although unexpected, this result is in line with the findings that aging can impair Nrf2 signalling in RPE after an acute oxidative insult [42].”
ResultLin, Y., Horng, L., Sung, H., & Wu, R.-T. (2018) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2017.0073 · Cited by 24 · see citing works
“18 The RPE damage is associated with increased levels of reactive oxygen species (ROS) both in vitro 19 and in vivo , 20 and several oxidative stress regulatory pathways, such as PTEN, 21 Nrf2, 20 and mTOR, 22 are involved.”
The Role of Nrf2/sMAF Signalling in Retina Ageing and Retinal Diseases
Zhang, J., Zhang, T., Zeng, S., Zhang, X., Zhou, F., Gillies, M. C., & Zhu, L. (2023) · Biomedicines · doi:10.3390/biomedicines11061512 · Cited by 23 · see citing works
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“Furthermore, aging is also well-connected with the loss of Nrf2 activity as evidenced by the impaired Nrf2 signaling in the retinal pigment epithelium of aging mice (4) and declines in stress resistance abilities and life span (5).”
BackgroundZhao, J., Kim, H. J., & Sparrow, J. R. (2017) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.17-21557 · Cited by 22 · see citing works
“22 When oxidative stress is induced with NaIO3, an age-related increase in superoxide anion and malondialdehyde is observed.(13) It is also reported”
BackgroundMimura, T., & Noma, H. (2025) · Antioxidants · doi:10.3390/antiox14101251 · Cited by 21 · see citing works
Desgarnier, M. D., Zinflou, C., Mallet, J. D., Gendron, S. P., Méthot, S. J., & Rochette, P. J. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.16-19878 · Cited by 21 · see citing works
Moro, T., Nakao, S., Sumiyoshi, H., Ishii, T., Miyazawa, M., Ishii, N., Sato, T., Iida, Y., Okada, Y., Tanaka, M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0146592 · Cited by 21 · see citing works
“In addition, an aging cell is generally known to exhibit high levels of oxidative stress [25], and a recent study reported that the Nrf2 signaling, which serves as a master regulator of a highly coordinated antioxidant response, is impaired in aged mice despite the age-related increase in basal oxidative stress, sugge…”
BackgroundStanhope, S. C., Brandwine-Shemmer, T., Blum, H. R., Doud, E. H., Jannasch, A., Mosley, A. L., Minke, B., & Weake, V. M. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102723 · Cited by 20 · see citing works
“For example, ROS signaling induces protective gene expression programs by releasing and activating the transcription factor Nrf2 [14], or by inhibiting activity of epigenetic factors such as the histone methyltransferase Set1/MLL via intramolecular disulfide bond formation [15].”
Background
- Authors
- Sachdeva, M. M., Cano, M., & Handa, J. T.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Handa, James T.
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 119
- Pages
- 111-114
- ISSN
- 0014-4835 (ISSN-L)
- PMC
- PMC3946784
- OpenAlex
- W2036704550
- Cited by
- 207
- References
- 18
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 15 · 2023: 22 · 2022: 28 · 2021: 25 · 2020: 29 · 2019: 21 · 2018: 10 · 2017: 13 · 2016: 13 · 2015: 8 · 2014: 2
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Eye Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NEI (EY019904, EY14005)
- Thome Foundation Award in AMD
- RPB Senior Scientist Award
- Wilmer Core Grant (EY001765)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- Nrf2 signaling, retinal pigment epithelium, aging, age-related macular degeneration, oxidative stress, sodium iodate, Keap1, antioxidant response, NQO1, GCLM, heme oxygenase-1, superoxide, malondialdehyde, genetic rescue
- MeSH terms
- Aging, Animals, Humans, Macular Degeneration, Signal Transduction, Oxidative Stress, NF-E2-Related Factor 2, Retinal Pigment Epithelium
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