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Activating the Nrf2 pathway with nutrition: what you need to know

Article at a Glance
  • When our cells use energy, the end product is the production of free radicals.
  • An excess of free radicals create oxidative stress, which has been linked to many chronic health conditions.
  • The Nrf2 pathway, is a genetic pathway that turns on over 200 genes, many of which are related to detoxification, such as GSTP1. In health, Nrf2 is activated by oxidative stress, but there are also nutrients that can activate Nrf2.
  • Among the most potent activators of Nrf2 is sulforaphane, a compound found in great abundance in broccoli sprouts.
Genes Mentioned
Nrf2 Pathway Activation Nutrition

We’ve discussed oxidative stress and free radicals in various posts on the Gene Food blog, often focusing on specific enzymes produced by the body such as superoxide dismutase 2 (SOD2), or specific beneficial nutrients such as glutathione. These direct acting enzymes and nutrients are great at fighting the fire of oxidative stress, but where this is a chronic condition, understanding how best to activate these antioxidants in the body is of great interest.

Before we dive into the importance of the Nrf2 pathway, we’ll go over a little primer on what happens when our bodies generate energy at the cellular level.

Cellular energy generation produces free radicals

Most compounds and molecules in our body exist in a relatively stable state, this is why we need enzymes (think of them as molecular power tools) to break them down or turn them into other more useful molecules.

However, some reactions in the body lead to the formation of molecules called free radicals (including reactive oxygen species and peroxides), most notably those involved in energy generation within the cell. Put another way, the byproduct of energy metabolism are damaging free radicals.

These free radicals are chemically unstable, and highly reactive. Two common examples are O2 sometimes called superoxide and H2O2 or hydrogen peroxide. O2 is the normal stable form of oxygen, however when involved in some reactions in the body O2 is formed. That little sign means that an extra electron has been added. Superoxide is therefore highly reactive as it is trying to find a way to lose that extra electron, and the only way to do that is to transfer it to another molecule or compound.

This is where antioxidants step in, it’s their function to mop up these highly reactive species making sure they don’t interact with any of the important molecules in a cell. This mopping up occurs constantly in the body, however, when antioxidant function in the body becomes overwhelmed by free radicals, oxidative stress can occur (R).

It is important to understand that free radicals in themselves are not bad, their formation is part and parcel of cellular energy generation, and they serve a vital role in other functions such as bacterial killing (R). So your aim should never be to remove free radicals, but rather ensure your system is in balance.

Oxidative stress and disease

In the short term, oxidative stress is unlikely to be harmful, as whilst the body may be temporarily overwhelmed it will usually respond and clear any harmful compounds.

However chronic oxidative stress is associated with several diseases including Parkinson’s disease (R), Alzheimer’s disease (R), cardiovascular disease (R) and several cancers (R). The exact impact is hard to pin down due to the long time scales involved in the development of these diseases, but it is an area of very active research.

Other major areas of interest are dietary and environmental exposures. At a base level things like alcohol and tobacco or a meat rich diet can increase oxidative stress. However, these are relatively easy to avoid and if you’re reading this blog chances are you’re already making positive health choices. There are other factors however which are more difficult to avoid such as air pollution (R), excessive exposure to pesticides (R), herbicides (R) or heavy metals (R). In these cases chronic oxidative stress can be generated, leaving existing anti-oxidant defences overwhelmed.

Fighting chronic oxidative stress

So we know that molecules such as glutathione are great at mopping up free radicals on a one to one basis, and that enzymes such as the SOD or glutathione peroxidase (GPX) enzyme families can rapidly reduce oxidative stress. But what happens in a chronic system where these defenses have been overwhelmed?

Enter Nrf2

Nuclear factor erythroid 2 [NF-E2]-related factor 2, known by the much easier to remember acronym Nrf2 is a transcription factor which is a major regulator of cell protective, including antioxidant, responses (R). Transcription factors are a class of protein which bind to DNA and induce the expression of particular genes, in the case of Nrf2, these are potent antioxidants such as NAD(P)H:quinone oxidoreductase 1 (NQO1) (R) and glutathione S-transferases (GSTs), and many others, as shown in the table below (R).

Cytoprotective gene products regulated by Keap1-Nrf2

Table 1 – Genes activated by NRF2. Adapted from: Baird, L. and Dinkova-Kostova, A.T. Arch. Toxicol. 85,241-272 (2011)

Nrf2 in health

In health, Nrf2 exists in the cytosol of a cell, or the region outside of the nucleus where it cannot interact with DNA. It is held here by another protein called Keap1, which prevents it moving into the nucleus (R).

Nrf2 activation

Keap1 contains several sensors for reactive oxygen species, along with receptor regions for other cell proteins associated with cell stress (R). If these receptors are activated then Nrf2 is released, and can pass into the nucleus (R).

Once within the nucleus Nrf2 binds to a region of DNA known as an “Antioxidant Response Element” or ARE (R). These ARE elements are closely associated with the genes for NQO1 and the GSTs (and many other genes) as discussed above, and when Nrf2 binds it induces the production of active proteins from these genes. Both of these proteins exhibit potent antioxidant capacity and can rapidly clear oxidative stress.

The Keap1-Nrf2 antioxidant pathway

Figure 1 – Nrf2 activation. Adapted from: May, O.L. Cayman Chemical (2012)

The important role for Nrf2 has been shown by several studies with a particular focus on animal models. Mice which have been genetically engineered to lack Nrf2 protein are considerably more sensitive to chemical carcinogens, and also chemical toxins leading to increased inflammation in the lung and brain, all major markers of oxidative stress.

Foods and supplements that activate Nrf2

While oxidative stress alone is able to activate Nrf2, its effect is greatly enhanced by the presence of certain chemical compounds.

The simplest of these compounds were identified as 1,4-benzenediol (hydroquinone), tert-butylhydroquinone, and 1,2-benzendiol (catechol), and more complex examples include the isothiocyanate sulforaphane from broccoli seed extract, curcumin from the turmeric plant and carotenoids such as zeaxanthin and lutein. All are complex in name and structure, but they share a common function in that they support increased and prolonged expression of Nrf2 gene targets (R, R).

Issues with Nrf2 activation

Whilst Nrf2 activation is undoubtedly beneficial in the vast majority of cases, there are some instances where it may prove harmful. Once again using a mouse model, this time lacking Keap1, meaning that Nrf2 would be constantly activated, researchers demonstrated that severe health effects would develop (R). Additionally, mutations in the Nrf2 gene in human studies have been associated with an increased risk of cancer, with the authors proposing that constance Nrf2 activity, prevents anti-cancer targeted oxidative stress, allowing cancer cells to survive (R).

It is unlikely that dietary supplementation would ever induce such strong effects but it’s a useful example of how oxidative stress isn’t always bad. Importantly there are no currently reported SNPs in Nrf2 which impact on its function. A lack of variation in genes like this typically points to how important they are to life, however an alternative option is that Nrf2 has not been widely investigated.

Take-home message

The take home message in this instance is quite simple. Nrf2 is a potent modulator of antioxidant response and can rapidly target oxidative stressors. While Nrf2 responds to oxidative stress directly, certain key nutrients can improve this effect, the exact source of these nutrients varies widely but dark green and leafy vegetables (think spinach, kale and broccoli, especially the seed extract), or reddy vegetables and spices (saffron, tumeric or paprika) are a particularly rich source. Importantly these foods are also typically rich in direct antioxidants and display numerous other health benefits, so they are a great way to improve overall health.

See also: 10 Things I Learned Going Vegan for a Week

Aaron Gardner

Dr Aaron Gardner is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.

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35 Comments

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  1. Patricia says:

    I have been taking NRF2 for ten months. I take warfarin, I have my INR mesured every month – its fine but I have been told I shouldn’t take NRF2 with blood thinner. Is this true?

  2. Selena says:

    If you are saying that over activation of NRF2 is harmful can taking Protandim the NRF2 activator for extended periods be harmful?

  3. Mary Clark says:

    I would love info from anyone who has improvements in conditions by using nrf1and nrf2. Am using protandim and have heart problems (aging) also osteoarthritis andbeginning of memory problems. Any testimonies of improving any of these as well as lack of energy? Thanks

  4. Nicole, RVT says:

    Very interesting article. Nutrigenomics is an up and coming new trend. We now know that we can turn on good genes and turn off bad genes by phytonutrients and foods. So glad I have been familiar with Nrf2 activation for over 8 yrs now. My holistic veterinarian uses it in her practice with great results. The research that we saw on PubMed blew our minds. As you know, dogs have 7 times more oxidative stress than humans. That is why they age faster. When you activate their Nrf2 pathway thus you are reducing oxidative stress. When you reduce oxidative stress then you decrease inflammation and disease symptoms. I have 2 dogs outliving their terminal cancer diagnoses (given 1 year to live, that was 8 yrs ago) with a great quality of life. I have a horse that is soon to be 38 yrs old outliving his health issues. Pets don’t have placebo effects. Quality of life is key for our beloved pets as well. Nrf2 activation is key to helping them do so especially with the food they eat and the toxin they are exposed to daily. We put this tool in our protocol. My pets will never go without it. 🙂

  5. Peggy Mills says:

    I have seen benefits of Protandim as well for the past 4 years. I suffered from severe arthritis pain and have found great relief. My doc says I am the spitting image of a 20 year in all my numbers. It is not a miracle cure, but is a proven Nrf2 activator. Have hundreds of studies catalogued because I had to make sure it was the real deal for myself. Let me know if you want any of them!!! Peggy Mills

    • Ruth says:

      I would appreciate your catalogue of studies as I am trialing the supplement myself along with my 80 year old Mum, I can only find limited research on PubMed that supports it and need to convince my scientist brother that there are independent studies supporting its benefits for osteoarthritis and cardiovascular disease.

      • Joan Ruddell says:

        Have your brother log into Pubmed.gov and do a search on NRF2. There at over 9,600 scientific researched studies published on the topic.

    • Joan Ruddell says:

      As we know, Synthroid is a synthetic Thyroxin used to counteract hypothyroidism.. Thyroxin is necessary for energy production. Energy production mostly takes place in the mitochondria of our cells as part of the Kreb’s cycle.. Nrf1 is an activator for mitochondrial function. It’s a good idea to check with your pharmacist or Endochronologist first if you plan to take NRF1.
      NRF2 activator reduces oxidative stress in the cells.

  6. Betty says:

    So are you saying it can make my psorasis worse? I have been taking nrf2 and nrf1 protandim by lifevantage for 3wks and have seen no improvement and more spots.

    • Vickie says:

      Hello Betty. I too, take Protandim and it wasn’t until the 3rd month on the product that my Psoriasis was gone. It’s different for everyone and you must give it a chance to work. It’s not a miracle, but it will change your gene expression and make things better if you just give it time to work. I also know someone who had plaque psoriasis of the scalp. She was really young, used it for 2 weeks and not only is it cleared up, but her hair is growing back in the top of her head where the psoriasis had taken it out. So be patient. Sometimes people go through detoxification before the glory. I have extreme confidence that you will get the help you’re looking for too. I hope this helps.

    • Hi Betty,

      Sorry to hear about this, as someone who also has issues with psoriasis I understand where you’re coming from looking for help.

      So I looked into it and interestingly NRF2 actually seems to promote the growth of keratinocytes in forming the plaques associated with psoriasis.
      https://www.ncbi.nlm.nih.gov/pubmed/28576737

      I wouldn’t change anything based on this study as NRF2 likely does different things in different parts of the body.

  7. Deb Rojas says:

    Have you heard of Protandim? They market based on NRF2 and oxidative stress inhibitors. I hope I’m saying that correctly. It seems that food can also provide the substance, though. Just curious.

  8. Rosa Castillo says:

    Hi Aaron, I’ve just been diagnosed with the MTHFR gene mutation and recently heard about Nrf2 via finding out about Protandim which claims to be a Nrf2 activator.
    My questions are:
    Have you heard about this product and what do you know of it?
    Also:
    Would this product be helpful for someone with my gene mutation?
    Thanks,
    Rosa 🙂

    • Michael Spadaccini says:

      Hi Aaron,
      Interesting article re nrf2 activation. As an 8 year user of a glutathione (our bodies endogenous master anti oxidant) precursor, developed by a world reknown scientist & medicinal chemist & world authority on glutathione. I, and thousands of others have gained very satisfactory results re all forms of oxidative stress.
      I won’t mention product, scientist or company on your forum, but I would like to know of your understanding of glutathione & its value to us?
      If I may share the basics of the protocol, the invention was 25yrs in the making, the inventor & his team were very successfully able to wrap the fragile rate limiting cysteine molecule with riboceine, to protect it through the gut, into the cell whereby the cysteine molecule remained in the cell to do its thing & the ribose enters the mitochondria as energy. The invention contains supporting ingredients such as broccoli seed extract, which has the highest concentration of the active ingredient sulforaphane glucosinolate, which is the same product used in studies by Johns Hopkins University of Medicine.
      In light of nrf2 activation combating oxidative stress, glutathione as the bodies master anti oxidant is at the forefront of this protective process, along with its capability to very successfully eliminate toxins.
      With 40% to 50% of the American populace, and even higher rates of the Asian community having the MTHFR gene mutation. Do you see it as paramount for ALL to have more than adequate levels of cellular glutathione?
      As a layman in the world of health (I’m a builder), I genuinely have gained & witnessed many fantastic results on this protocol, and simply wish to share the wonderful invention of a remarkable scientist, that has spent 25yrs of lab work, failing, until he & his team finally cracked the protocol to very successfully allow each & every cell within us, to be able to absorb the precursors too allow those cells to manufacture glutathione.
      I look forward to any comment or thought you may have Aaron re the bodies master anti oxidant.

      • Dan Mahony says:

        Hi Michael,

        I have been doing Iv and oral Glutathione on and off over the last couple of years as well as NAC. I’d be interested if you could please share the info about the product you mention above as I’m low in energy due to having Lyme disease. Thanks

    • Michael Spadaccini says:

      Hi Rosa,
      With 40% to 50% of Americans, and an even greater number of Asian’s having MTHFR gene mutation, may I suggest you google MTHFR & glutathione together in a search. Preferably go to pubmed to see the scientific research available. If you find the information credible, I would like to share with you a scientifically proven & natural protocol that will increase your intracellular glutathione safely & very effectively.
      Best wishes
      Michael Spadaccini

  9. Annette Gayle says:

    I am delighted to find like-minded individuals, especially doctors, who understand the power of nrf2 activation. I have used it successfully to slow my 82 year old aunt’s dementia to a crawl for the last 3 years and my 7 year old granddaughter’s vitiligo is reversing itself! We now have over 750 doctors who have joined our company including one of the top 50 preventative cardiologists in the world. Forgive my excitement but this is my mission, to educate as many as possible about regaining a quality of life with nrf2 activation. We currently have over 20 peer-reviewed studies on our all natural product and over 1,000,000 people world wide using it daily. I’m happy to provide more information on it if you would like. Thanks for educating on this medical breakthrough!

  10. Daina Van Duynhoven says:

    Don, I just read your article in Pub Med. I am extremely interested in hearing about any follow up research you and your team are doing since this article was released. I am a dietitian and am just getting my feet wet in the world of Nrf2. I am incredibly interested in all of the potential your research discovered. Thank you so much to you and your colleagues for completing this study.

  11. Don Senger says:

    Hi Aaron,
    I enjoyed reading your post that brings much needed attention to the Nrf2 Cell Defense Pathway. Recently, my colleagues and I published an article in PLoS ONE that describes previously unrecognized, natural Nrf2 activation by compounds found it ancient foods but absent from modern diets. Here’s the link to the online version: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148042

    In particular, our data point to foods and beverages traditionally fermented with plant-associated lactobacilli as important dietary sources of Nrf2 activators. Although there has been much written about the importance of diet, fermented foods, and probiotics for general health, I believe our data provide important, previously unrecognized connections with Nrf2. They also explain critical differences between various “probiotic” bacteria, – specifically, that only the wild plant lactobacilli can produce Nrf2 activators and that lactobacilli used for fermenting dairy products lack the necessary enzymes.

    I hope you find this of interest and welcome any questions.

    • Hi Don,

      Sorry for the slow reply about this. I’ve just read through your paper, really interesting seeing the extent to which you can activate Nrf2. I think it will be really interesting to see the effects of such foods on people with disorders such as IBD/Celiacs as you can see a virtuous cycle here. Improve gut flora, reduce inflammation and so on.

      I found the comments about coffee particularly interesting as this is something that we’re very often told to avoid. Do you have any idea how your doses of chlorogenic acid and caffeic acid relate to those people might actually see in their diet?

      • Don Senger says:

        Hi Aaron,
        Thanks for your comment and question. Chlorogenic acid and caffeic acid are found in a wide variety of fruits and vegetables. But it’s generally agreed that apples and coffee have the highest levels. Our more recent work (not yet published) indicates that Lactobacillus plantarum probiotic, taken twice/day – in combination with any diet that contains two servings/day of coffee or apple products – does indeed reduce inflammation.

        • Thanks Don, that sounds like very interesting research. Would love to see it when you’ve published it. Getting an anti-microbial/anti-inflammatory response from your two cups of coffee would be very nice!

  12. Christine Houghton says:

    I notice you use a broccoli seed extract in your formulation containing 40 mg SGS. Are you aware that this is NOT sulforaphane. It is actually the glucoraphanin precursor which requires the myrosinase enzyme to produce sulforaphane. SGS supplements rely the unpredictable, highly-variable and inconsistent effects of the gut microflora to make this conversion. There may be only 8-10% conversion (or even none) so that 40 mg SGS may produce only 3-4 mg sulforaphane. Many clinical trials with successful outcomes rely on around 20 mg daily. Why not use a 100% whole broccoli sprout material that retains its myrosinase enzyme?

    • Hi Christine, thanks for your comment. I wasn’t aware that there were supplements available that can maintain myrosinase enzyme function following the extraction process? Would be very interested to read a mechanism for that if you know of one?

      I guess another issue are the potential health issues associated with excess myrosinase activity as described here:

      http://www.nejm.org/doi/full/10.1056/NEJMc0911005

      Obviously most people don’t each 1-1.5 kg of bok choi every day for several month, but this could be an issue with improper supplementation?

      • Christine Houghton says:

        Hi Aaron, The paper you sent is about mature crucifers which generate goitrogens. Broccoli sprouts don’t produce the goitrogens which are present in the mature broccoli vegetable. To follow on from my earlier post, I must declare a potential conflict of interest in that we are the Australian manufacturers of EnduraCell, a 100% whole broccoli sprout raw material which retains its myrosinase activity along with the glucoraphanin. As a whole plant, it is not an extract and so there is no extraction process for which a mechanism can be described. We manufacture in a way that adds nothing and removes nothing but water. Every batch of raw material is assayed in an independent U.S. laboratory, so we know the potency of the product.

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