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Frontiers in Medical Science Research, 2021, 3(2); doi: 10.25236/FMSR.2021.030204.

Clinical Research Progress of NRF2 Activators in the Treatment of Age-related Diseases


Man Xu

Corresponding Author:
Man Xu

College of Life and Environment Sciences, Wenzhou University, Wenzhou 325035, China


Oxidation is closely related to the occurrence and development of aging and age-related diseases. NRF2 (Nuclear factor erythroid 2 related factor 2) is a key regulator of oxidative stress, which regulates the expression of antioxidant proteins, detoxification enzymes and various cytoprotective proteins. NRF2 maintains organism redox balance and genome stability, delaying the aging process and the occurrence and development of aging-related diseases. Pharmacological activators of NRF2 has been widely reported in basic research, and has performed well in clinical application research. In this article, we will focus on the latest news in basic and clinical research of NRF2 activators in age related diseases.


NRF2, aging, oxidative stress, age-related diseases, NRF2 activators

Cite This Paper

Man Xu. Clinical Research Progress of NRF2 Activators in the Treatment of Age-related Diseases. Frontiers in Medical Science Research (2021) Vol. 3 Issue 2: 10-16. https://doi.org/10.25236/FMSR.2021.030204.


[1] R. M, Evolutionary perspectives on ageing, Seminars in cell & developmental biology, 2017, 70, 99-107.

[2] M. D, P. LC and F. L, The genetics of human ageing, Nature reviews. Genetics, 2020, 21, 88-101.

[3] P. L, D. J and S. PE, Facing up to the global challenges of ageing, Nature, 2018, 561, 45-56.

[4] C. A, M. G, H. A, A. MJ, B. C, D. A, G. P, L. R, L. MG, O. B, P. M, R. AI, R.-A. N, V. AM, G. E and S. HHHW, Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach, Pharmacological reviews, 2018, 70, 348-383.

[5] Q. Ma, Role of nrf2 in oxidative stress and toxicity, Annu Rev Pharmacol Toxicol, 2013, 53, 401-426.

[6] K. TW, W. N and B. S, Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway, Annual review of pharmacology and toxicology, 2007, 47, 89-116.

[7] T. W, W. H, L. S, L. Q and S. H, The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases, Aging and disease, 2019, 10, 637-651.

[8] Q. Liu, Y. Gao and X. Ci, Role of Nrf2 and Its Activators in Respiratory Diseases, Oxid Med Cell Longev, 2019, 2019, 7090534.

[9] C. A, R. AI, W. G, H. JD, C. SP, R. WL, A. OC, F. S, L. AL, K. TW and D.-K. AT, Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases, Nature reviews. Drug discovery, 2019, 18, 295-317.

[10] C. AR, G. AA, J. R, R. MR, M. LJ, L. JZ, A. M, R. Y, D. T, W. J, L. CJ and H. WA, Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury, Arteriosclerosis, thrombosis, and vascular biology, 2012, 32, 2839-2846.

[11] V. D, L. Z, M. PM, S. E, W. N, D. YP, L. MP, K. TW and G. F, Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence, Molecular biology of the cell, 2013, 24, 1852-1862.

[12] G. Shanmugam, M. Narasimhan, R. L. Conley, T. Sairam, A. Kumar, R. P. Mason, R. Sankaran, J. R. Hoidal and N. S. Rajasekaran, Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling, Front Physiol, 2017, 8, 268.

[13] Y. M, K. TW and M. H, The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis, Physiological reviews, 2018, 98, 1169-1203.

[14] L. Q, X. S, C. Y, L. Q, L. Q, L. Y, H. S, F. F, C. Y, Z. J, L. W, G. Q, S. Y and S. H, Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases, European journal of medicinal chemistry, 2020, 185, 111862.

[15] C. Jo, S. Gundemir, S. Pritchard, Y. N. Jin, I. Rahman and G. V. Johnson, Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52, Nat Commun, 2014, 5, 3496.

[16] L. Bakota and R. Brandt, Tau Biology and Tau-Directed Therapies for Alzheimer's Disease, Drugs, 2016, 76, 301-313.

[17] D. W, Y. B, W. L, L. B, G. X, Z. M, J. Z, F. J, P. J, G. D and Z. R, Curcumin plays neuroprotective roles against traumatic brain injury partly via Nrf2 signaling, Toxicology and applied pharmacology, 2018, 346, 28-36.

[18] L. W, S. NC and P. S, Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R, Microvascular research, 2016, 106, 117-127.

[19] M. H. Rahman, R. Akter, T. Bhattacharya, M. M. Abdel-Daim, S. Alkahtani, M. W. Arafah, N. S. Al-Johani, N. M. Alhoshani, N. Alkeraishan, A. Alhenaky, O. H. Abd-Elkader, H. R. El-Seedi, D. Kaushik and V. Mittal, Resveratrol and Neuroprotection: Impact and Its Therapeutic Potential in Alzheimer's Disease, Front Pharmacol, 2020, 11, 619024.

[20] C. Moussa, M. Hebron, X. Huang, J. Ahn, R. A. Rissman, P. S. Aisen and R. S. Turner, Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease, J Neuroinflammation, 2017, 14, 1.

[21] W. Rathmann and G. Giani, Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabetes care, 2004, 27, 2568-2569; author reply 2569.

[22] A. K. Palmer, B. Gustafson, J. L. Kirkland and U. Smith, Cellular senescence: at the nexus between ageing and diabetes, Diabetologia, 2019, 62, 1835-1841.

[23] 23. M. M, F. K and H. EH, Activation of Nrf2 signaling by natural products-can it alleviate diabetes?, Biotechnology advances, 2018, 36, 1738-1767.

[24] L. M. Aleksunes, S. A. Reisman, R. L. Yeager, M. J. Goedken and C. D. Klaassen, Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice, The Journal of pharmacology and experimental therapeutics, 2010, 333, 140-151.

[25] M. S. Bitar and F. Al-Mulla, A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes, Am J Physiol Endocrinol Metab, 2011, 301, E1119-1129.

[26] U. A, F. Y, Y. Y, F. T, M. H, N. T, S. A, K. TW and Y. M, The Keap1-Nrf2 system prevents onset of diabetes mellitus, Molecular and cellular biology, 2013, 33, 2996-3010.

[27] C. D, Y. Y, S. A, D. CH, W. H, C. L and H. XF, Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet, Molecular and cellular endocrinology, 2015, 412, 36-43.

[28] D. GM, J. UJ, P. HJ, K. EY, J. SM, M. RA and C. MS, Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP-activated protein kinase and its downstream targets in db/db mice, Molecular nutrition & food research, 2012, 56, 1282-1291.

[29] T. Z, Z. LJ, M. PW, L. SP, C. SJ, F. XD and W. TH, Caveolin-3 is involved in the protection of resveratrol against high-fat-diet-induced insulin resistance by promoting GLUT4 translocation to the plasma membrane in skeletal muscle of ovariectomized rats, The Journal of nutritional biochemistry, 2012, 23, 1716-1724.

[30] S. Bo, V. Ponzo, A. Evangelista, G. Ciccone, I. Goitre, F. Saba, M. Procopio, M. Cassader and R. Gambino, Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial, Acta diabetologica, 2017, 54, 499-507.

[31] S. MY, K. EK, M. WS, P. JW, K. HJ, S. HS, P. R, K. KB and P. BH, Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway, Toxicology and applied pharmacology, 2009, 235, 57-67.

[32] Y. Panahi, N. Khalili, E. Sahebi, S. Namazi, Z. Reiner, M. Majeed and A. Sahebkar, Curcuminoids modify lipid profile in type 2 diabetes mellitus: A randomized controlled trial, Complement Ther Med, 2017, 33, 1-5.

[33] C. PR, C. G, H. G, G. M, V. MA and G. JR, Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells, Aging, 2013, 5, 913-924.

[34] S. Satta, A. M. Mahmoud, F. L. Wilkinson, M. Yvonne Alexander and S. J. White, The Role of Nrf2 in Cardiovascular Function and Disease, Oxid Med Cell Longev, 2017, 2017, 9237263.

[35] A. H, C. G, B. M, A. D, S. AC, M. SJ, D. MS, K. J, B. JJ, L. C, I. H, Y. A, S. NB, C. H, C. TJ, S. N, B. DR, B. RI, H. I, T. DA, L. J, L. CA, J. M, K. RK, N. S, R. C, d. C. R, A. I, T. M, G. UL, R. AJ, V. MR, P. PJ, T. DJ and W. H, Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway, Cell metabolism, 2012, 15, 361-371.

[36] C. JW, E. M, N. CK, G. S, J. S, E. JW, R. A and L. DJ, Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice, Circulation, 2010, 122, 11-19.

[37] G. R, L. B, W. K, Z. S, L. W and X. Y, Resveratrol ameliorates diabetic vascular inflammation and macrophage infiltration in db/db mice by inhibiting the NF-κB pathway, Diabetes & vascular disease research, 2014, 11, 92-102.

[38] Z. X, Z. S, C. S, C. Y, D. J, L. J, L. R and Z. Y, Protective effects of chronic resveratrol treatment on vascular inflammatory injury in streptozotocin-induced type 2 diabetic rats: Role of NF-kappa B signaling, European journal of pharmacology, 2013, DOI: 10.1016/j.ejphar.2013.10.034.

[39] U. Z, B. Z, F. A, R. FA, S. WE, P. K, d. C. R and C. A, Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2, American journal of physiology. Heart and circulatory physiology, 2010, 299, H18-24.

[40] M. X, C. W, S. W, X. Y, W. B, T. Y, C. L, M. L, F. Y, S. G and W. Y, Therapeutic effect of MG132 on the aortic oxidative damage and inflammatory response in OVE26 type 1 diabetic mice, Oxidative medicine and cellular longevity, 2013, 2013, 879516.

[41] A.-M. E, G. D, B. S, H. A, B. V, M.-S. J, A. ZE, C. B, K.-R. S, B. A and B. M, Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis, Antioxidants & redox signaling, 2013, 18, 66-79.