NrF2: The Anti-Oxidant Amplifier
Oxidative stress is a major player in the formation of pathological conditions such as cancer, diabetes, heart disease, accelerated aging and neurodegeneration. Anti-oxidant 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.
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 anti-oxidant 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 anti-oxidant 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 auto-immune 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 auto-immune 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 adviseable to consume these compounds everyday to keep anti-oxidant 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 metasisis (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.
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