Activate the Antioxidant Benefits of Nrf2
Oxidative stress is a major player in the formation of pathological conditions such as cancer, diabetes, heart disease, accelerated aging and neurodegeneration. Antioxidant rich foods, herbs and supplements are used to protect the body from unwanted oxidative stress. Recent research has found a new signaling pathway that plays an enormous role in amplifying the effects of anti-oxidants on the body. In this article, you will discover 5 ways to activate the antioxidant benefits of the Nrf2 gene pathway.
The body adapts to function in a state of homeostasis or balance. When the body is confronted with major stressors the cells must quickly modulate their antioxidant capacity to counteract the increased oxidative stress. In order to do this the body is able to activate a massive antioxidant effect in a matter of nanoseconds through a specific genetic pathway.
The Keap1-Nrf2 Pathway and Your Health:
Nrf2 (NF-E2-related factor 2) is a transcription factor in humans encoded by a specific gene that regulates the expression of a set of antioxidant and detoxifying genes. This pathway is activated under times of oxidative stress to enhance the expression of a multitude of antioxidant and phase II liver detoxification enzymes that restore homeostasis to the ox/redox cycles in the body (1, 2, 3).
An enzyme named (Keap1) which sits on the cytosol of the cell interacts with Nrf2 and activates it. Keap1 is rich in the amino acid cysteine, and acts as a sensor that is constantly reading the environment for any increase or decrease in oxidative stress. Under times of increased stress, Keap1 activates Nrf2 which then migrates into the cell nucleus and bonds to the DNA to active the Antioxidant Response Element (ARE). ARE then upregulates a variety of powerful antioxidant enzymes and detoxifying proteins (4, 5, 6).
This Keap1-Nrf2 pathway regulates over 600 genes involved in cellular protection and anti-oxidant defenses. These various genes act to boost major antioxidant and detoxifying enzymes such as glutathione and superoxide dismutase. They also promote anti-inflammatory prostaglandins and enzymes and improve tissue healing and repair (7, 8).
Nrf2 and Cancer Prevention:
High levels of oxidative stress damage normal cells, affecting the DNA and inducing cancer causing mutations. Oxidative stress also activates chronic inflammatory pathways that create an optimal environment for cancer development. The Keap1-Nrf2 pathway has been shown to be protective against tumor formation (9, 10).
Nrf2 has a dark side in that cancer cells can use a mutated form of this pathway to protect themselves against the bodies immune system and chemotherapeutic agents. Mutations in the Keap1-Nrf2 pathway can lead to fast growing and highly resistant tumor growths (11, 12).
Nrf2 and Brain Health:
We have an epidemic of neurodegenerative disorders in the western world. The Keap1-Nrf2-ARE pathway has been researched to be a key player in the development or prevention of neurodegeneration (11, 12, 13)
Additionally, mood disorders such as depression, bipolar, addictions, etc. have shown to be linked to chronic inflammation. The Nrf2 pathway has been researched to be a major factor in the development of mood disorders and poor neurotransmitter function (14, 15, 16).
Nrf2 and Diabetes Prevention:
Type II diabetes is characterized by chronic inflammation and oxidative stress. Diabetes is also the major cause of chronic kidney disease and peripheral neuropathy worldwide. It is also a major factor in the formation of cardiovascular disease. Research has indicated that the Nrf2 pathway is markedly reduced in type II diabetes and this is associated with hyperglycemia and the heavy formation of advanced glycolytic end products that provoke tissue damage (17, 18).
Research has indicated that having stability in the Keap1 and Nrf2 pathway is crucial to the prevention of type II diabetes (19, 20). Activating the Keap1 and Nrf2 pathway is also protective to the body against the tremendous metabolic stress that diabetes creates (21). Additionally, the pathway helps to stabilize blood sugar levels and reverse some of the damage of this disorder (22, 23).
Nrf2 and Auto-Immunity:
The Keap1-Nrf2 pathway appears to play an important role in proper immune coordination. Studies observing Nrf2 deficient mice have shown that they are at great risk of developing a wide-variety of autoimmune disorders including lupus, multiple sclerosis, hemolytic anemia, rheumatoid arthritis and many others (24, 25, 26, 27, 28).
Nrf2 deficient mice developed normal body structures but they displayed a variety of autoimmune disorders and a shortened lifespan. It is thought that the decreased glutathione production from the Nrf2 deficient mice leads to immune malcoordination and hyperinflammatory processes.
Nrf2 and Hormonal Health:
Aging and high levels of physical, chemical and emotional stress are associated with the loss of progesterone in women and testosterone in men. When these key hormones are depleted it causes a state of estrogen dominance. This state of estrogen dominance is one of the major factors associated with degenerative disease processes (29, 30, 31).
Estrogen dominance can lead to menstrual and menopausal issues in women. This includes the following major health issues:
The Keap1-Nrf2 pathway regulates the expression of antioxidant enzymes such as glutathione perioxidase and NAD(P)H-quinone oxidoreductase 1 that help to remove toxic estrogen metabolites (32, 33). This is extremely critical due to the ubiquitous nature of artificial estrogen molecules in our society.
Estrogen is a growth factor and stimulates growth patterns in many forms of breast, uterine, cervical, ovarian, prostate and colon cancers. Research has shown that activation of the Nrf2 pathway inhibits the estrogen signaling pathway in various forms of breast cancer (34, 35).
There are several compounds that can be found in nature and ingested through specific foods and herbs that enhance the Keap1-Nrf2 pathway. The most powerful nutrients that support the activation of the anti-oxidant amplifying Nrf2 pathway include curcumin, stilbenes, catechins, and sulforaphane.
You can find these nutrients in turmeric (curcumin), resveratrol in grape skin and berries (stilbenes), green tea and dark chocolate (catechins) and cruciferous veggies (sulforaphane). It is highly advisable to consume these compounds everyday to keep antioxidant systems in balance. This will result in positive adaptations that improve aging, reduce disease formation and improve quality of life.
There is also benefit to consuming these ingredients together as they have a synergetic effect that amplifies their effects on the Keap1-Nrf2 pathway. The easiest way this is done is through key supplements that are specifically designed to upregulate this pathway.
From a food and nutritional perspective, one could have steamed Brussel sprouts with grass-fed butter (fat-soluble carrier) or coconut oil melted on top. Add generous amounts of turmeric to the dish, broccoli sprouts and a pinch of black pepper. Consume this with green tea and some red wine. Finish with a small bite of minimally processed dark chocolate.
Turmeric and Curcumin:
The orange Asian herb turmeric has been traditionally used for centuries by Ayurveda and Chinese medicine. Curcumin is the most powerful active anti-inflammatory compound within turmeric. Curcumin has been shown to be a powerful suppressor of chronic inflammatory mediated disease processes.
Curcumin has been shown to reduce inflammatory mediating prostaglandins, cytokines and other molecules such as interleukin 6, Nuclear Factor Kappa Beta (NF-kb) and tumor necrosis factor-alpha (TNF – alpha) (36,37). With a high enough dosage this has the ability to pull the body out of a strong inflammatory cascade and reset anti-inflammatory behavior at the cellular level.
Curcumin exerts both direct and indirect antioxidant effects by scavenging reactive oxygen species (ROS)(38) and inducing the expression of cytoprotective proteins in an Nrf2-dependent way (39). Human studies showed a significant increase in curcumin absorption when co-administered with black pepper extract.
This is the compound found in cruciferous veggies and most densely in broccoli sprouts. SFN was identified as a chemopreventive agent over a decade ago on the basis of its capability to induce phase II detoxification enzymes, and to inhibit phase I enzymes involved in the activation of carcinogens (40).
Research demonstrates that sulforaphane, through induction of Nrf2-dependent phase 2 enzymes, protects the brain against hypoxic-ischemic injury and may improve cognitive function when administered following traumatic brain injury (41, 42). Additionally, it protect the brain from neurodegenerative states and amyloid plaque buildup as seen in the pathogenesis of Alzheimer’s disease (43, 44)
Pterostilbene – Resveratrol:
This is a naturally occurring phenolic compound/analog of resveratrol that has comparatively better oral bioavailability, has been shown to possess cytotoxic, cytokine-inhibiting, and antioxidant properties (45). This compound has also been shown to slow the process of aging by reducing telomerase activity (46).
Resveratrol has also been shown to increase the protein and mRNA expression of Nrf2. There is evidence that Nrf2-mediated attenuation of oxidative stress and cytokine induction could be partially responsible for resveratrol’s potential effect on cell-life regulation (47). This compound has profound effects on regulating estrogen metabolism and inducing cancer cell apoptosis (48)
In rat and animal studies, resveratrol/pterostilbene have been shown to upregulate a significant number of genes involved in mitochondrial function as well as to modulate cholinergic neurotransmission and improve cognition (49)
Green tea is rich in the polyphenol anti-oxidant catechin called epigallocatechin-3-gallate (EGCG). This anti-oxidant is thought by most to be responsible for the health benefits linked to green tea consumption. EGCG has been identified to have a profound effect on the Nrf2-ARE pathway (50)
Research has shown that EGCG stimulates the Nrf2 anti-oxidant activity in immune cells, liver and intestinal cells (51, 52). Through this mechanism it also modulates cancer cell proliferation, differentiation, apoptosis, adhesion, angiogenesis and metastasis (53, 54).
A study published in December 2004 in Cancer Research discussed how ECGC in green tea was able to decrease insulin-like growth factor-1 (IGF-1) while increasing levels of IGF binding protein-3, which binds IGF-1. This reduces the risk of breast, colon, prostate & lung cancer. It also inhibits key cancer survival proteins and reduces the expression of compounds associated with cancer metastasis (55).
My Favorite NrF2 Enhancing Supplement:
As a clinician, I believe this supplement is the best way to boost antioxidant defenses by increasing the activity of the Nrf2 pathway and positively affecting the development of antioxidant genes.
I use this supplement with all of my chronic disease patients and those that have chronic inflammation. It is also something I personally take to prevent inflammation and improve my overall performance.
Sources for This Article Include:
1. Kang KW, Lee SJ, Kim SG. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1664-73. PMID: 16356128
2. Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys. 2005 Jan 15;433(2):342-50. Review. PMID: 15581590
3. Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.Planta Med. 2008 Oct;74(13):1526-39. PMID: 18937164
4. Nguyen T, Yang CS, Pickett CB. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med. 2004 Aug 15;37(4):433-41. Review. PMID: 15256215
5. Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):385-94. Review. PMID: 15706085
6. Hybertson BM, Gao B, Bose SK, McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2. Mol Aspects Med. 2011 Aug;32(4-6):234-46. Review PMID: 22020111
7. Vriend J, Reiter RJ. The Keap1-Nrf2-antioxidant response element pathway: A review of its regulation by melatonin and the proteasome.Mol Cell Endocrinol. 2014 Dec 17;401C:213-220. Review. PMID: 25528518
8. Giudice A, Arra C, Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemo preventive agents. Methods Mol Biol. 2010;647:37-74. PMID: 20694660
9. Slocum SL, Kensler TW. Nrf2: control of sensitivity to carcinogens.Arch Toxicol. 2011 Apr;85(4):273-84. PMID: 21369766
10. Kwak MK, Kensler TW. Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol. 2010 Apr 1;244(1):66-76. PMID: 19732782
11. Miller DM, Singh IN, Wang JA, Hall ED. Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumaticbrain injury in mice.Exp Neurol. 2014 Nov 26;264C:103-110. PMID: 25432068
12. Kärkkäinen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J. Nrf2regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells. 2014 Jul;32(7):1904-16. PMID: 24753106
13. Sandberg M, Patil J, D’Angelo B, Weber SG, Mallard C. NRF2-regulation in brain health and disease: implication of cerebral inflammation. 2014 Apr;79:298-306. Review. PMID: 24262633
14. Bakunina N, Pariante CM, Zunszain PA. Immune mechanisms linked to depression via oxidative stress and neuroprogression.2015 Jan 10. PMID: 25580634
15. Martín-de-Saavedra MD, Budni J, Cunha MP, Gómez-Rangel V, Lorrio S, Del Barrio L, Lastres-Becker I, Parada E, Tordera RM, Rodrigues AL, Cuadrado A, López MG. Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. 2013 Oct;38(10):2010-22. PMID: 23623252
16. Lee SY, Lee SJ, Han C, Patkar AA, Masand PS, Pae CU. Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants.Prog Neuropsychopharmacol Biol Psychiatry. 2013 Oct 1;46:224-35. Review. PMID: 23022673
18. Uruno A, Yagishita Y, Yamamoto M. The Keap1-Nrf2system and diabetes mellitus. Arch Biochem Biophys. PMID: 25528168
19. Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M. The Keap1-Nrf2system prevents onset of diabetes mellitus. Mol Cell Biol. 2013 Aug;33(15):2996-3010. PMID: 23716596
20. Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, Uruno A, Yamamoto M. Nrf2protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice. 2014 Feb;63(2):605-18. PMID: 24186865
21. Bhakkiyalakshmi E, Sireesh D, Rajaguru P, Paulmurugan R, Ramkumar KM. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol Res. 2015 Jan;91C:104-114. PMID: 25447793
23. Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD.Therapeutic potential ofNrf2 activators in streptozotocin-induced diabetic nephropathy. 2011 Nov;60(11):3055-66. PMID: 22025779
24. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S. Nrf2-deficient female mice develop lupus-like autoimmune nephritis.Kidney Int. 2001 Oct;60(4):1343-53. PMID: 11576348
25. Bernstein AI, Miller GW. Oxidative signaling inexperimental autoimmune encephalomyelitis.Toxicol Sci. 2010 Apr;114(2):159-61 PMID: 20234054
26. Li J, Stein TD, Johnson JA.Geneticdissectionof systemic autoimmune disease in Nrf2-deficient mice. Physiol Genomics. 2004 Aug 11;18(3):261-72. PMID: 15173550
27. Lee JM, Chan K, Kan YW, Johnson JA. Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9751-6. PMID: 15210949
28. Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmuneinflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol. 2006 Jun;168(6):1960-74. PMID: 16723711
29. Jankowska EA, Rogucka E, Medraś M, Welon Z. Relationships between age-related changes of sex steroids, obesity and body fat distribution among healthy Polish males.Med Sci Monit. 2000 Nov-Dec;6(6):1159-64. PMID: 11208473
30. Morale MC, L’Episcopo F, Tirolo C, Giaquinta G, Caniglia S, Testa N, Arcieri P, Serra PA, Lupo G, Alberghina M, Harada N, Honda S, Panzica GC, Marchetti B. Loss of aromatase cytochrome P450 function as a risk factor for Parkinson’s disease?Brain Res Rev. 2008 Mar;57(2):431-43. PMID: 18063054
31. Machioka K, Mizokami A, Yamaguchi Y, Izumi K, Hayashi S, Namiki M. Active Estrogen Synthesis and its Function in Prostate Cancer-derived Stromal Cells. Anticancer Res. 2015 Jan;35(1):221-7. PMID: 25550554
32. Montano MM, Bianco NR, Deng H, Wittmann BM, Chaplin LC, Katzenellenbogen BS. Estrogen receptor regulation of quinone reductase in breast cancer: implications for estrogen-induced breast tumor growth and therapeutic uses of tamoxifen. Front Biosci. 2005 May 1;10:1440-61. PMID: 15769636
33. Montano MM, Jaiswal AK, Katzenellenbogen BS. Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor-alpha and estrogen receptor-beta.J Biol Chem. 1998 Sep 25;273(39):25443-9. PMID: 9738013
34. Yao Y, Brodie AM, Davidson NE, Kensler TW, Zhou Q. Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer. Breast Cancer Res Treat. 2010 Nov;124(2):585-91. PMID: 20623181
35. Singh B, Chatterjee A, Ronghe AM, Bhat NK, Bhat HK. Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer.BMC Cancer. 2013 May 22;13:253. PMID: 23697596
36. Chen C, Yu R, Owuor ED, Kong AN. Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major greentea polyphenol components during cell survival and death.Arch Pharm Res. 2000 Dec;23(6):605-12. PMID: 11156183
37. Andreadi CK, Howells LM, Atherfold PA, Manson MM. Involvementof Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction ofhemeoxygenase-1 by dietary polyphenols. Mol Pharmacol. 2006 Mar;69(3):1033-40. PMID: 16354769
38. Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, Wung BS. Upregulation of heme oxygenase-1 by Epigallocatechin-3 gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci. 2006 May 15;78(25):2889-97. PMID: 16378625
39. Na HK, Surh YJ. Intracellular signaling network as a prime chemopreventive target of (-)-epigallocatechin gallate. Mol Nutr Food Res. 2006 Feb;50(2):152-9. Review. PMID: 16470647
40. Tachibana H. Molecular basis for cancer chemoprevention by green tea polyphenol EGCG.Forum Nutr. 2009;61:156-69. PMID: 19367120
41. Lee KH, Abas F, Alitheen NB, Shaari K, Lajis NH, Ahmad S. A curcumin derivative, 2,6-bis(2,5-dimethoxybenzylidene)-cyclohexanone (BDMC33) attenuates prostaglandin E2 synthesis via selective suppression of cyclooxygenase-2 in IFN-γ/LPS-stimulated macrophages. 2011 Nov 23;16(11):9728-38. PMID: 22113581
42. Seyedzadeh MH, Safari Z, Zare A, Gholizadeh Navashenaq J, Razavi SA, Kardar GA, Khorramizadeh MR.Study of curcumin immunomodulatory effects on reactive astrocyte cell function. Int Immunopharmacol. 2014 Sep;22(1):230-5. PMID: 24998635
43. Sreejayan, Rao MN. Nitric oxide scavenging by curcuminoids.J Pharm Pharmacol. 1997 Jan;49(1):105-7. PMID: 9120760
44. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, Motterlini R. Curcuminactivates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 2003 May 1;371(Pt 3):887-95. PMID: 12570874
45. Myzak MC, Dashwood RH. Chemoprotection by sulforaphane: keep one eye beyond Keap1.Cancer Lett. 2006 Feb 28;233(2):208-18. Review. PMID: 16520150
46. Hong Y, Yan W, Chen S, Sun CR, Zhang JM. The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumaticbrain injury in rats and mice. Acta Pharmacol Sin. 2010 Nov;31(11):1421-30. PMID: 20953205
47. Tarozzi A, Angeloni C, Malaguti M, Morroni F, Hrelia S, Hrelia P. Sulforaphaneas a potential protective phytochemical against neurodegenerative diseases. Oxid Med Cell Longev. 2013;2013:415078. PMID: 23983898
48. Zhang R, Miao QW, Zhu CX, Zhao Y, Liu L, Yang J, An L. SulforaphaneAmeliorates Neurobehavioral Deficits and Protects the Brain From Amyloid β Deposits and Peroxidation in Mice With Alzheimer-Like Lesions. Am J Alzheimers Dis Other Demen. 2014 Jul 13. PMID: 25024455
49. Zhang R, Zhang J, Fang L, Li X, Zhao Y, Shi W, An L. Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer’s disease-like lesions.Int J Mol Sci. 2014 Aug 18;15(8):14396-410.. PMID: 25196440
50. Sato D, Shimizu N, Shimizu Y, Akagi M, Eshita Y, Ozaki S, Nakajima N, Ishihara K, Masuoka N, Hamada H, Shimoda K, Kubota N. Synthesis of glycosides ofresveratrol, pterostilbene, and piceatannol, and their anti-oxidant, anti-allergic, and neuroprotective activities. Biosci Biotechnol Biochem. 2014;78(7):1123-8. PMID: 25229845
51. Tippani R, Prakhya LJ, Porika M, Sirisha K, Abbagani S, Thammidala C. Pterostilbeneas a potential novel telomerase inhibitor: molecular docking studies and its in vitro evaluation. Curr Pharm Biotechnol. 2014;14(12):1027-35. PMID: 24433502
52. Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G.Low-dosepterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease. Neurobiol Aging. 2012 Sep;33(9):2062-71. PMID: 21982274
53. Singh B, Shoulson R, Chatterjee A, Ronghe A, Bhat NK, Dim DC, Bhat HK.Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways. 2014 Aug;35(8):1872-80. PMID: 24894866
54. Acharya JD, Ghaskadbi SS. Protective effect of Pterostilbene against free radical mediated oxidative damage.BMC Complement Altern Med. 2013 Sep 26;13:238. PMID: 24070177
55. Tachibana H. Molecular basis for cancer chemoprevention by green tea polyphenol EGCG. Forum Nutr. 2009;61:156-69. PMID: 19367120