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Lability of the Nrf2/Keap/ARE Cell Defense System in Different Models of Cell Aging and Age-Related Pathologies

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Abstract

The level of oxidative stress in an organism increases with age. Accumulation of damages resulting in the disruption of genome integrity can be the cause of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this regard, the Nrf2 system, which regulates expression of numerous enzymes responsible for the antioxidant defense and detoxification, is of great interest. This review summarizes and analyzes the data on the age-related changes in the Nrf2 system in vivo and in vitro in various organs and tissues. Analysis of published data suggests that the capacity for Nrf2 activation (triggered by the increased level of oxidative stress) steadily declines with age. At the same time, changes in the Nrf2 activity under the stress-free conditions do not have such unambiguous directionality; in many studies, these changes were statistically insignificant, although it is commonly accepted that the level of oxidative stress steadily increases with aging. This review examines the role of cell regulatory systems limiting the ability of Nrf2 to respond to oxidative stress. Senescent cells are extremely susceptible to the oxidative damage due to the impaired Nrf2 signaling. Activation of the Nrf2 pathway is a promising target for new pharmacological or genetic therapeutic strategies. Suppressors of the Nrf2 expression, such as Keap1, GSK3, c-Myc, and Bach1, may contribute to the age-related impairments in the induction of Nrf2-regulated antioxidant genes. Understanding the mechanisms of regulatory cascades linking the programs responsible for the maintenance of homeostasis and cell response to the oxidative stress will contribute to the elucidation of molecular mechanisms underlying aging and longevity.

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Abbreviations

ARE:

antioxidant response element

Bach1:

BTB domain and CNC homolog 1

Gcl:

glutamate-cysteine ligase

Gclc:

glutamate-cysteine ligase catalytic subunit

Gclm:

glutamate-cysteine ligase modifier subunit

GSK3:

glycogen synthase kinase 3

Ho-1:

heme oxygenase 1

Keap1:

Kelch-like ECH-associated protein 1

Nqo1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

nuclear factor erythroid 2-related factor 2

NSPC:

neural stem progenitor cell

PDL:

population doubling level

ROS:

reactive oxygen species

RPE:

retinal pigment epithelium

VSMC:

vascular smooth muscle cell

References

  1. Skulachev, M. V., Severin, F. F., and Skulachev, V. P. (2015) Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival, Curr. Aging Sci., 8, 95-109, https://doi.org/10.2174/1874609808666150422122401.

    Article  PubMed  Google Scholar 

  2. Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., et al. (2017) Neoteny, prolongation of youth: From naked mole rats to “naked apes” (humans), Physiol. Rev., 97, 699-720, https://doi.org/10.1152/physrev.00040.2015.

    Article  PubMed  Google Scholar 

  3. Skulachev, V. P. (2019) Phenoptosis as a phenomenon widespread among many groups of living organisms including mammals (Commentary to the paper by E. R. Galimov, J. N. Lohr, and D. Gems (2019), Biochemistry (Moscow), 84, 1433-1437), Biochemistry (Moscow), 84, 1438-1441, https://doi.org/10.1134/S0006297919120022.

    Article  CAS  Google Scholar 

  4. Skulachev, V. P., Shilovsky, G. A., Putyatina, T. S., Popov, N. A., Markov, A. V., et al. (2020) Perspectives of Homo sapiens lifespan extension: focus on external or internal resources?, Aging (Albany NY), 12, 5566-5584, https://doi.org/10.18632/aging.102981.

    Article  Google Scholar 

  5. Lewis, K. N., Wason, E., Edrey, Y. H., Kristan, D. M., Nevo, E., et al. (2015) Regulation of Nrf2 signaling and longevity in naturally long-lived rodents, Proc. Natl. Acad. Sci. USA, 112, 3722-3727, https://doi.org/10.1073/pnas.1417566112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vyssokikh, M. Y., Holtze, S., Averina, O. A., Lyamzaev, K. G., Panteleeva, A. A., et al. (2020) Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program, Proc. Natl. Acad. Sci. USA, 117, 6491-6501, https://doi.org/10.1073/pnas.1916414117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cuadrado, A. (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP, Free Radic. Biol. Med., 88, 147-157, https://doi.org/10.1016/j.freeradbiomed.2015.04.029.

    Article  CAS  PubMed  Google Scholar 

  8. Duan, W. S., Zhang, R. Y., Guo, Y. S., Jiang, Y. F., Huang, Y. L., et al. (2009) Nrf2 activity is lost in the spinal cord and its astrocytes of aged mice, In vitro Cell. Dev. Biol. Anim., 45, 388-397, https://doi.org/10.1007/s11626-009-9194-5.

    Article  CAS  PubMed  Google Scholar 

  9. Shilovsky, G. A., Putyatina, T. S., Morgunova, G. V., Seliverstov, A. V., Ashapkin, V. V., et al. (2021) A crosstalk between the biorhythms and gatekeepers of longevity: Dual role of glycogen synthase kinase-3, Biochemistry (Moscow), 86, 433-448, https://doi.org/10.1134/S0006297921040052.

    Article  CAS  Google Scholar 

  10. Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., et al. (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease, Free Radic. Biol. Med., 88, 108-146, https://doi.org/10.1016/j.freeradbiomed.2015.06.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., et al. (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription, Nat. Commun., 7, 11624, https://doi.org/10.1038/ncomms11624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Suh, J. H., Shenvi, S. V., Dixon, B. M., Liu, H., Jaiswal, A. K., et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid, Proc. Natl. Acad. Sci. USA, 101, 3381-3386, https://doi.org/10.1073/pnas.0400282101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Safdar, A., deBeer, J., and Tarnopolsky, M. A. (2010) Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old, Free Radic. Biol. Med., 49, 1487-1493, https://doi.org/10.1016/j.freeradbiomed.2010.08.010.

    Article  CAS  PubMed  Google Scholar 

  14. Ungvari, Z., Bailey-Downs, L., Sosnowska, D., Gautam, T., Koncz, P., et al. (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response, Am. J. Physiol. Heart Circ. Physiol., 301, 363-372, https://doi.org/10.1152/ajpheart.01134.2010.

    Article  CAS  Google Scholar 

  15. Ungvari, Z., Bailey-Downs, L., Gautam, T., Sosnowska, D., Wang, M., et al. (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-κB activation in the nonhuman primate Macaca mulatta, J. Gerontol. A Biol. Sci. Med. Sci., 66, 866-875, https://doi.org/10.1093/gerona/glr092.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang, H., Davies, K. J. A., and Forman, H. J. (2015) Oxidative stress response and Nrf2 signaling in aging, Free Radic. Biol. Med., 88 (Pt. B), 314-336, https://doi.org/10.1016/j.freeradbiomed.2015.05.036.

    Article  CAS  Google Scholar 

  17. Xu, S. F., Ji, L. L., Wu, Q., Li, J., and Liu, J. (2018) Ontogeny and aging of Nrf2 pathway genes in livers of rats, Life Sci., 203, 99-104, https://doi.org/10.1016/j.lfs.2018.04.018.

    Article  CAS  PubMed  Google Scholar 

  18. Tomobe, K., Shinozuka, T., Kuroiwa, M., and Nomura, Y. (2012) Age-related changes of Nrf2 and phosphorylated GSK-3β in a mouse model of accelerated aging (SAMP8), Arch. Gerontol. Geriatr., 54, 1-7, https://doi.org/10.1016/j.archger.2011.06.006.

    Article  CAS  Google Scholar 

  19. Shih, P. H., and Yen, G. C. (2007) Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway, Biogerontology, 8, 71-80, https://doi.org/10.1007/s10522-006-9033-y.

    Article  CAS  PubMed  Google Scholar 

  20. Smith, E. J., Shay, K. P., Thomas, N. O., Butler, J. A., Finlay, L. F., et al. (2015) Age-related loss of hepatic Nrf2 protein homeostasis: potential role for heightened expression of miR-146a, Free Radic. Biol. Med., 89, 1184-1191, https://doi.org/10.1016/j.freeradbiomed.2015.11.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou, L., Zhang, H., Davies, K. J. A., and Forman, H. J. (2018) Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells, Redox Biol., 14, 35-40, https://doi.org/10.1016/j.redox.2017.08.014.

    Article  CAS  PubMed  Google Scholar 

  22. Baek, M. K., Lee, H., Kim, K. O., Kwon, H. J., Chung, M. H., et al. (2017) Age-related changes in nuclear factor erythroid 2-related factor 2 and reactive oxygen species and mitochondrial structure in the tongues of Fischer 344 rats, Clin. Exp. Otorhinolaryngol., 10, 357-362, https://doi.org/10.21053/ceo.2016.01095.

    Article  CAS  PubMed  Google Scholar 

  23. Gounder, S. S., Kannan, S., Devadoss, D., Miller, C. J., Whitehead, K. J., et al. (2012) Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training, PLoS One, 7, e45697, https://doi.org/10.1371/journal.pone.0045697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ungvari, Z., Tarantini, S., Kiss, T., Wren, J. D., Giles, C. B., et al. (2018) Endothelial dysfunction and angiogenesis impairment in the ageing vasculature, Nat. Rev. Cardiol., 15, 555-565, https://doi.org/10.1038/s41569-018-0030-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fulop, G. A., Kiss, T., Tarantini, S., Balasubramanian, P., Yabluchanskiy, A., et al. (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation, GeroScience, 40, 513-521, https://doi.org/10.1007/s11357-018-0047-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. George, L., Lokhandwala, M. F., and Asghar, M. (2009) Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats, Am. J. Physiol. Renal Physiol., 297, 1174-1180, https://doi.org/10.1152/ajprenal.00397.2009.

    Article  CAS  Google Scholar 

  27. Li, M., Liu, R. M., Timblin, C. R., Meyer, S. G., Mossman, B. T., et al. (2006) Age affects ERK1/2 and Nrf2 signaling in the regulation of GCLC expression, J. Cell Physiol., 206, 518-525.

    Article  CAS  Google Scholar 

  28. Sachdeva, M. M., Cano, M., and Handa, J. T. (2014) Nrf2 signaling is impaired in the aging RPE given an oxidative insult, Exp. Eye Res., 119, 111-114, https://doi.org/10.1016/j.exer.2013.10.024.

    Article  CAS  PubMed  Google Scholar 

  29. Wu, D. M., Ji, X., Ivanchenko, M. V., Chung, M., Piper, M., et al. (2021) Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa, JCI Insight, 6, e145029, https://doi.org/10.1172/jci.insight.145029.

    Article  PubMed Central  Google Scholar 

  30. Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., and Cuadrado, A. (2019) Activators and inhibitors of NRF2: a review of their potential for clinical development, Oxid. Med. Cell. Longev., 2019, 9372182, https://doi.org/10.1155/2019/9372182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bose, C., Alves, I., Singh, P., Palade, P. T., Carvalho, E., et al. (2020) Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling, Aging Cell, 19, e13261, https://doi.org/10.1111/acel.13261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Alarcón-Aguilar, A., Luna-López, A., Ventura-Gallegos, J. L., Lazzarini, R., Galván-Arzate, S., et al. (2014) Primary cultured astrocytes from old rats are capable to activate the Nrf2 response against MPP+ toxicity after tBHQ pretreatment, Neurobiol. Aging, 35, 1901-1912, https://doi.org/10.1016/j.neurobiolaging.2014.01.143.

    Article  CAS  PubMed  Google Scholar 

  33. Miller, C. J., Gounder, S. S., Kannan, S., Goutam, K., Muthusamy, V. R., et al. (2012) Disruption of Nrf2/ARE signaling impairs antioxidant mechanisms and promotes cell degradation pathways in aged skeletal muscle, Biochim. Biophys. Acta, 1822, 1038-1050, https://doi.org/10.1016/j.bbadis.2012.02.007.

    Article  CAS  PubMed  Google Scholar 

  34. Kitaoka, Y., Tamura, Y., Takahashi, K., Takeda, K., Takemasa, T., et al. (2019) Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle, Physiol. Rep., 7, e13998, https://doi.org/10.14814/phy2.13998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, D., Zhao, H., Cui, Z. K., and Tian, G. (2021) The role of Nrf2 in hearing loss, Front. Pharmacol., 12, 620921, https://doi.org/10.3389/fphar.2021.620921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hosokawa, K., Hosokawa, S., Ishiyama, G., Ishiyama, A., and Lopez, I. A. (2018) Immunohistochemical localization of Nrf2 in the human cochlea, Brain Res., 1700, 1-8, https://doi.org/10.1016/j.brainres.2018.07.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hoshino, T., Tabuchi, K., Nishimura, B., Tanaka, S., Nakayama, M., et al. (2011) Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity, Biochem. Biophys. Res. Commun., 415, 94-98, https://doi.org/10.1016/j.bbrc.2011.10.019.

    Article  CAS  PubMed  Google Scholar 

  38. Honkura, Y., Matsuo, H., Murakami, S., Sakiyama, M., Mizutari, K., et al. (2016) Nrf2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea, Sci. Rep., 6, 19329, https://doi.org/10.1038/srep19329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Valcarcel-Ares, M. N., Gautam, T., Warrington, J. P., Bailey-Downs, L., Sosnowska, D., et al. (2012) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging, J. Gerontol. A Biol. Sci. Med. Sci., 67, 821-829, https://doi.org/10.1093/gerona/glr229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kapeta, S., Chondrogianni, N., and Gonos, E. S. (2010) Nuclear erythroid factor 2-mediated proteasome activation delays senescence in human fibroblasts, J. Biol. Chem., 285, 8171-8184, https://doi.org/10.1074/jbc.M109.031575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jódar, L., Mercken, E. M., Ariza, J., Younts, C., González-Reyes, J. A., et al. (2011) Genetic deletion of Nrf2 promotes immortalization and decreases life span of murine embryonic fibroblasts, J. Gerontol. A Biol. Sci. Med. Sci., 66, 247-256, https://doi.org/10.1093/gerona/glq181.

    Article  CAS  PubMed  Google Scholar 

  42. Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., et al. (2017) Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism, Aging Cell, 16, 564-574, https://doi.org/10.1111/acel.12587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lerner, C., Bitto, A., Pulliam, D., Nacarelli, T., Konigsberg, M., et al. (2013) Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts, Aging Cell, 12, 966-977, https://doi.org/10.1111/acel.12122.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang, Y., Unnikrishnan, A., Deepa, S. S., Liu, Y., Li, Y., et al. (2017) A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1–/– mice is correlated to increased cellular senescence, Redox Biol., 11, 30-37, https://doi.org/10.1016/j.redox.2016.10.014.

    Article  CAS  PubMed  Google Scholar 

  45. Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., et al. (2016) Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period, Aging Cell, 15, 725-736, https://doi.org/10.1111/acel.12482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Volonte, D., Liu, Z., Musille, P. M., Stoppani, E., Wakabayashi, N., et al. (2013) Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence, Mol. Biol. Cell, 24, 1852-1862, https://doi.org/10.1091/mbc.E12-09-0666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kubben, N., Zhang, W., Wang, L., Voss, T. C., Yang, J., et al. (2016) Repression of the antioxidant Nrf2 pathway in premature aging, Cell, 165, 1361-1374, https://doi.org/10.1016/j.cell.2016.05.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Orr, W. C., Radyuk, S. N., Prabhudesai, L., Toroser, D., Benes, J. J., et al. (2005) Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster, J. Biol. Chem., 280, 37331-37338, https://doi.org/10.1074/jbc.M508272200.

    Article  CAS  PubMed  Google Scholar 

  49. Jasper, H. (2008) SKNy worms and long life, Cell, 132, 915-916, https://doi.org/10.1016/j.cell.2008.03.002.

    Article  CAS  PubMed  Google Scholar 

  50. Bruns, D. R., Drake, J. C., Biela, L. M., Peelor, F. F. 3rd, Miller, B. F., et al. (2015) Nrf2 signaling and the slowed aging phenotype: evidence from long-lived models, Oxid. Med. Cell. Longev., 2015, 732596, https://doi.org/10.1155/2015/732596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Silva-Palacios, A., Ostolga-Chavarría, M., Buelna-Chontal, M., Garibay, C., Hernández-Reséndiz, S., et al. (2017) 3-NP-induced Huntington’s-like disease impairs Nrf2 activation without loss of cardiac function in aged rats, Exp. Gerontol., 96, 89-98, https://doi.org/10.1016/j.exger.2017.06.009.

    Article  CAS  PubMed  Google Scholar 

  52. Morin, P. Jr, Ni, Z., McMullen, D. C., and Storey, K. B. (2008) Expression of Nrf2 and its downstream gene targets in hibernating 13-lined ground squirrels, Spermophilus tridecemlineatus, Mol. Cell. Biochem., 312, 121-129, https://doi.org/10.1007/s11010-008-9727-3.

    Article  CAS  PubMed  Google Scholar 

  53. Levy, S., and Forman, H. J. (2010) C-Myc is a Nrf2-interacting protein that negatively regulates phase II genes through their electrophile responsive elements, IUBMB Life, 62, 237-246, https://doi.org/10.1002/iub.314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jain, A. K., and Jaiswal, A. K. (2007) GSK3β acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2, J. Biol. Chem., 282, 16502-16510, https://doi.org/10.1074/jbc.M611336200.

    Article  CAS  PubMed  Google Scholar 

  55. Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., et al. (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation, Nat. Genet., 35, 238-425, https://doi.org/10.1038/ng1248.

    Article  CAS  PubMed  Google Scholar 

  56. Sykiotis, G. P., and Bohmann, D. (2010) Stress-activated cap‘n’collar transcription factors in aging and human disease, Sci. Signal., 3, re3, https://doi.org/10.1126/scisignal.3112re3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Castiglione, G. M., Xu, Z., Zhou, L., and Duh, E. J. (2020) Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds, Nat. Commun., 11, 2476, https://doi.org/10.1038/s41467-020-16129-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rahman, M. M., Sykiotis, G. P., Nishimura, M., Bodmer, R., and Bohmann, D. (2013) Declining signal dependence of Nrf2-MafS-regulated gene expression correlates with aging phenotypes, Aging Cell, 12, 554-562, https://doi.org/10.1111/acel.12078.

    Article  CAS  PubMed  Google Scholar 

  59. Kopacz, A., Klóska, D., Proniewski, B., Cysewski, D., Personnic, N., et al. (2020) Keap1 controls protein S-nitrosation and apoptosis–senescence switch in endothelial cells, Redox Biol., 28, 101304, https://doi.org/10.1016/j.redox.2019.101304.

    Article  CAS  PubMed  Google Scholar 

  60. Kloska, D., Kopacz, A., Cysewski, D., Aepfelbacher, M., Dulak, J., et al. (2019) Nrf2 sequesters Keap1 preventing podosome disassembly: a quintessential duet moonlights in endothelium, Antioxid. Redox Signal, 30, 1709-1730, https://doi.org/10.1089/ars.2018.7505.

    Article  CAS  PubMed  Google Scholar 

  61. Palsamy, P., Bidasee, K. R., Ayaki, M., Augusteyn, R. C., Chan, J. Y., et al. (2014) Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts, Free Radic. Biol. Med., 72, 134-148, https://doi.org/10.1016/j.freeradbiomed.2014.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cloer, E. W., Goldfarb, D., Schrank, T. P., Weissman, B. E., and Major, M. B. (2019) NRF2 activation in cancer: from DNA to protein, Cancer Res., 79, 889-898, https://doi.org/10.1158/0008-5472.CAN-18-2723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dhakshinamoorthy, S., Jain, A. K., Bloom, D. A., and Jaiswal, A. K. (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants, J. Biol. Chem., 280, 16891-16900, https://doi.org/10.1074/jbc.M500166200.

    Article  CAS  PubMed  Google Scholar 

  64. Tian, X., Cong, F., Guo, H., Fan, J., Chao, G., and Song, T. (2019) Downregulation of Bach1 protects osteoblasts against hydrogen peroxide-induced oxidative damage in vitro by enhancing the activation of Nrf2/ARE signaling, Chem. Biol. Interact., 309, 108706, https://doi.org/10.1016/j.cbi.2019.06.019.

    Article  CAS  PubMed  Google Scholar 

  65. Yamaoka, M., Shimizu, H., Takahashi, T., Omori, E., and Morimatsu, H. (2017) Dynamic changes in Bach1 expression in the kidney of rhabdomyolysis-associated acute kidney injury, PLoS One, 12, e0180934, https://doi.org/10.1371/journal.pone.0180934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Meng, D., Wang, X., Chang, Q., Hitron, A., Zhang, Z., et al. (2010) Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism, Toxicol. Appl. Pharmacol., 244, 291-299, https://doi.org/10.1016/j.taap.2010.01.004.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, H., Liu, H., Davies, K. J., Sioutas, C., Finch, C. E., et al. (2012) Nrf2-regulated phase II enzymes are induced by chronic ambient nanoparticle exposure in young mice with age-related impairments, Free Radic. Biol. Med., 52, 2038-2046, https://doi.org/10.1016/j.freeradbiomed.2012.02.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shenvi, S. V., Smith, E., and Hagen, T. M. (2012) Identification of age-specific Nrf2 binding to a novel antioxidant response element locus in the Gclc promoter: a compensatory means for the loss of glutathione synthetic capacity in the aging rat liver?, Aging Cell, 11, 297-304, https://doi.org/10.1111/j.1474-9726.2011.00788.x.

    Article  CAS  PubMed  Google Scholar 

  69. Jiang, T., Harder, B., Rojo de la Vega, M., Wong, P. K., Chapman, E., et al. (2015) p62 links autophagy and Nrf2 signaling, Free Radic. Biol. Med., 88 (Pt. B), 199-204, https://doi.org/10.1016/j.freeradbiomed.2015.06.014.

    Article  CAS  Google Scholar 

  70. Kwon, J., Han, E., Bui, C. B., Shin, W., Lee, J., et al. (2012) Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade, EMBO Rep., 13, 150-156, https://doi.org/10.1038/embor.2011.246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bitto, A., Lerner, C. A., Nacarelli, T., Crowe, E., Torres, C., et al. (2014) P62/SQSTM1 at the interface of aging, autophagy, and disease, Age (Dordr.), 36, 9626, https://doi.org/10.1007/s11357-014-9626-3.

    Article  CAS  Google Scholar 

  72. Iwahana, E., Hamada, T., Uchida, A., and Shibata, S. (2007) Differential effect of lithium on the circadian oscillator in young and old hamsters, Biochem. Biophys. Res. Commun., 354, 752-756, https://doi.org/10.1016/j.bbrc.2007.01.042.

    Article  CAS  PubMed  Google Scholar 

  73. Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., et al. (2017) In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains, Sci. Rep., 7, 8602, https://doi.org/10.1038/s41598-017-09239-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zmijewski, J. W., and Jope, R. S. (2004) Nuclear accumulation of glycogen synthase kinase-3 during replicative senescence of human fibroblasts, Aging Cell, 3, 309-317, https://doi.org/10.1111/j.1474-9728.2004.00117.x.

    Article  CAS  PubMed  Google Scholar 

  75. Hoshi, M., Takashima, A., Noguchi, K., Murayama, M., Sato, M., et al. (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain, Proc. Natl. Acad. Sci. USA, 93, 2719-2723, https://doi.org/10.1073/pnas.93.7.2719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Salcedo-Tello, P., Ortiz-Matamoros, A., and Arias, C. (2011) GSK3 function in the brain during development, neuronal plasticity, and neurodegeneration, Int. J. Alzheimer’s Dis., 11, 1-12, https://doi.org/10.4061/2011/189728.

    Article  Google Scholar 

  77. Iitaka, C., Miyazaki, K., Akaike, T., and Ishida, N. (2005) A role for glycogen synthase kinase-3β in the mammalian circadian clock, J. Biol. Chem., 280, 29397-29402, https://doi.org/10.1074/jbc.M503526200.

    Article  CAS  PubMed  Google Scholar 

  78. Early, J. O., Menon, D., Wyse, C. A., Cervantes-Silva, M. P., Zaslona, Z., et al. (2018) Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2, Proc. Natl. Acad. Sci. USA, 115, 8460-8468, https://doi.org/10.1073/pnas.1800431115.

    Article  CAS  Google Scholar 

  79. Hiebert, P., Wietecha, M. S., Cangkrama, M., Haertel, E., Mavrogonatou, E., et al. (2018) Nrf2‐mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome, Dev. Cell, 46, 145-161.e10, https://doi.org/10.1016/j.devcel.2018.06.012.

    Article  CAS  PubMed  Google Scholar 

  80. Yuan, H., Xu, Y., Luo, Y., Wang, N. X., and Xiao, J. H. (2021) Role of Nrf2 in cell senescence regulation, Mol. Cell. Biochem., 476, 247-259, https://doi.org/10.1007/s11010-020-03901-9.

    Article  CAS  PubMed  Google Scholar 

  81. Kensler, T. W., Wakabayashi, N., and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway, Annu. Rev. Pharmacol. Toxicol., 47, 89-116, https://doi.org/10.1146/annurev.pharmtox.46.120604.141046.

    Article  CAS  PubMed  Google Scholar 

  82. Shanmugam, G., Narasimhan, M., Conley, R. L., Sairam, T., Kumar, A., et al. (2017) Chronic endurance exercise impairs cardiac structure and function in middle-aged mice with impaired Nrf2 signaling, Front. Physiol., 8, 268, https://doi.org/10.3389/fphys.2017.00268.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ahn, B., Pharaoh, G., Premkumar, P., Huseman, K., Ranjit, R., et al. (2018) Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass, Redox Biol., 17, 47-58, https://doi.org/10.1016/j.redox.2018.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nakagami, Y. (2016) Nrf2 is an attractive therapeutic target for retinal diseases, Oxid. Med. Cell. Longev., 2016, 7469326, https://doi.org/10.1155/2016/7469326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Vnukov, V. V., Gutsenko, O. I., Milutina, N. P., Kornienko, I. V., Ananyan, A. A., et al. (2015) Influence of SkQ1 on expression of Nrf2 gene, are-controlled genes of antioxidant enzymes and their activity in rat blood leukocytes under oxidative stress, Biochemistry (Moscow), 80, 1598-1605, https://doi.org/10.1134/S0006297915120081.

    Article  CAS  Google Scholar 

  86. Vnukov, V. V., Gutsenko, O. I., Milyutina, N. P., Kornienko, I. V., Ananyan, A. A., et al. (2017) SkQ1 regulates expression of Nrf2, ARE-controlled genes encoding antioxidant enzymes, and their activity in cerebral cortex under oxidative stress, Biochemistry (Moscow), 82, 942-952, https://doi.org/10.1134/S0006297917080090.

    Article  CAS  Google Scholar 

  87. Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., et al. (2018) Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach, Pharmacol. Rev., 70, 348-383, https://doi.org/10.1124/pr.117.014753.

    Article  CAS  PubMed  Google Scholar 

  88. Brandes, M. S., and Gray, N. E. (2020) NRF2 as a therapeutic target in neurodegenerative diseases, ASN Neuro, 12, 1759091419899782, https://doi.org/10.1177/1759091419899782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cui, L., Zhou, Q., Zheng, X., Sun, B., and Zhao, S. (2020) Mitoquinone attenuates vascular calcification by suppressing oxidative stress and reducing apoptosis of vascular smooth muscle cells via the Keap1/Nrf2 pathway, Free Radic. Biol. Med., 161, 23-31, https://doi.org/10.1016/j.freeradbiomed.2020.09.028.

    Article  CAS  PubMed  Google Scholar 

  90. Zinovkin, R. A., and Grebenchikov, O. A. (2020) Transcription factor Nrf2 as a potential therapeutic target for prevention of cytokine storm in COVID-19 patients, Biochemistry (Moscow), 85, 833-837, https://doi.org/10.1134/S0006297920070111.

    Article  CAS  Google Scholar 

  91. Hushpulian, D. M., Ammal Kaidery, N., Ahuja, M., Poloznikov, A. A., Sharma, S. M., et al. (2021) Challenges and limitations of targeting the Keap1-Nrf2 pathway for neurotherapeutics: Bach1 de-repression to the rescue, Front. Aging Neurosci., 13, 673205, https://doi.org/10.3389/fnagi.2021.673205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P., and Sobolev, A. S. (2021) Keap1/ARE signaling: Towards specific regulation, Life Sci., 291, 120111, https://doi.org/10.1016/j.lfs.2021.120111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Farré, X., Molina, R., Barteri, F., Timmers, P. R. H. J., Joshi, P. K., et al. (2021) Comparative analysis of mammal genomes unveils key genomic variability for human life span, Mol. Biol. Evol., 38, 4948-4961, https://doi.org/10.1093/molbev/msab219.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Holtze, S., Gorshkova, E., Braude, S., Cellerino, A., Dammann, P., et al. (2021) Alternative animal models of aging research, Front. Mol. Biosci., 8, 660959, https://doi.org/10.3389/fmolb.2021.660959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Miskevich, D., Chaban, A., Dronina, M., Abramovich, I., Gottlieb, E., et al. (2021) Comprehensive analysis of 13C6 Glucose fate in the hypoxiatolerant blind mole rat skin fibroblasts, Metabolites, 11, 734, https://doi.org/10.3390/metabo11110734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Miskevich, D., Chaban, A., Dronina, M., Abramovich, I., Gottlieb, E., et al. (2021) Glutamine homeostasis and its role in the adaptive strategies of the blind mole rat, Spalax, Metabolites, 11, 755, https://doi.org/10.3390/metabo11110755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Omotoso, O., Gladyshev, V. N., and Zhou, X. (2021) Lifespan extension in long-lived vertebrates rooted in ecological adaptation, Front. Cell Dev. Biol., 9, 704966, https://doi.org/10.3389/fcell.2021.704966.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Podder, A., Raju, A., and Schork, N. J. (2021) Cross-species and human inter-tissue network analysis of genes implicated in longevity and aging reveal strong support for nutrient sensing, Front. Genet., 12, 719713, https://doi.org/10.3389/fgene.2021.719713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dontsov, A. E., Sakina, N. L., Yakovleva, M. A., Bastrakov, A. I., Bastrakova, I. G., et al. (2020) Ommochromes from the compound eyes of insects: Physicochemical properties and antioxidant activity, Biochemistry (Moscow), 85, 668-678, https://doi.org/10.1134/S0006297920060048.

    Article  CAS  Google Scholar 

  100. Omran, B., and Baek, K. H. (2021) Nanoantioxidants: Pioneer types, advantages, limitations, and future insights, Molecules, 26, 7031, https://doi.org/10.3390/molecules26227031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ushakova, N. A., Brodsky, E. S., Tikhonova, O. V., Dontsov, A. E., Marsova, M. V., et al. (2021) Novel extract from beetle Ulomoides dermestoides: a study of composition and antioxidant activity, Antioxidants (Basel), 10, 1055, https://doi.org/10.3390/antiox10071055.

    Article  CAS  Google Scholar 

  102. Egea, J., Buendia, I., Parada, E., Navarro, E., Cuadrado, P., et al. (2015) Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a “drug-prodrug” mechanism of action, Br. J. Pharmacol., 172, 1807-1821, https://doi.org/10.1111/bph.13025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gameiro, I., Michalska, P., Tenti, G., Cores, Á., Buendia, I., et al. (2017) Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease, Sci. Rep., 7, 45701, https://doi.org/10.1038/srep45701.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Demuro, S., Di Martino, R. M. C., Ortega, J. A., and Cavalli, A. (2021) GSK-3β, FYN, and DYRK1A: Master regulators in neurodegenerative pathways, Int. J. Mol. Sci., 22, 9098, https://doi.org/10.3390/ijms22169098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The study was supported by the Russian Foundation for Basic Research (project no. 18-29-13037).

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  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    Gregory A. Shilovsky

  2. Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Gregory A. Shilovsky

  3. Institute for Information Transmission Problems, Russian Academy of Sciences, 127051, Moscow, Russia

    Gregory A. Shilovsky

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Shilovsky, G.A. Lability of the Nrf2/Keap/ARE Cell Defense System in Different Models of Cell Aging and Age-Related Pathologies. Biochemistry Moscow 87, 70–85 (2022). https://doi.org/10.1134/S0006297922010060

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