NrF2 and the Supplements that Boost This Antioxidant Pathway

Given the constant internal and external bombardment of our cells by oxidative stress, without a control system we would crumble under the biochemical strain. On the inside, our bodies produce countless reactive oxygen or nitrogen species which could damage other cell and tissue structures. From the outside, our fallen and inflammatory world creates another set of stressors that required a response by our bodies to avoid critical failure of our biochemistry. Without such systems our bodies fall to toxicities, chronic disease, and cancers. Nrf2 (nuclear factor erythroid 2 – related factor 2) serves this role quite well under normal conditions of level by activating a number of other pathways, but given the increasing toxic stresses of our world, knowing a few supplements to boost this pathway increases our chances of resisting the diseases associated with high oxidative stress.

This Nrf2 pathway responds to a variety of triggers, mainly oxidative stress triggers, but also to some herbals that we can choose to take. Once activated, Nrf2 induces a number of other enzymes like glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1). These secondary enzymes then participate directly in handling the increased oxidative stress which triggered the change in Nrf2. This works through “ARE-regulated DMEs” as “they catalyze a collection of heterogeneous reactions, including oxidation by CYP2A5, ALDH3A1, and ADH7; reduction by NQO1 and AKRs; conjugation by UGTs and SULT3A1; and nucleophilic trapping reactions by GSTs, mEH, and ES-10.” Even without knowing what these acronyms mean and what they do, you can appreciate that a lot happens downstream when Nrf2 is activated.

These enzymes then play a role in several processes of cells essential to life. Nrf2 supports autophagy in which older and more worn proteins or cells are broken down and recycled before they can cause dysfunction or disease. Nrf2 activation serves as an anti-inflammatory brake on various cellular inflammatory processes. Cells under high stress conditions leading to unfolding of proteins need Nrf2 to either help them restore balance or self-destruct before they spread their damage. Nrf2 serves to keep mitochondria, our cell’s powerhouses, from damage so they continue functioning. It is even necessary for stem cells, the cells we use to replenish worn out cells as we age.

Nrf2 plays a role in several well recognized disease processes. Tylenol toxicity severity is affected by Nrf2 activity. Alcoholic liver disease is influenced by the function of this Nrf2 pathway. The effects of smoke are modulated by the activity of Nrf2 in the lungs. In a complex variety of ways, Nrf2 function serves to protect against cancer. More and more research indicates a role of Nrf2 in neurodegenerative diseases like Alzheimer’s and multiple sclerosis.

In functional medicine, as we care for patients with inflammatory conditions such as infections or toxicities, we want to have tools in our therapy toolbox that can modify the Nrf2 pathway so that these conditions have as little effect as possible on our patients. Toxins, whether heavy metals, synthetics, or mold toxins, can all raise inflammation through a different pathway known as the NFkappaB or by directly damage cells and tissues. Infections whether bacterial like Lyme, Bartonella, and mycoplasma or viral like COVID19, EBV, HHV6, and HSV can also raise inflammation. We must respond by stopping the ongoing inflammatory damage and encouraging the healing of the damage already done.

As research continues to examine the proper use and dosing of Nrf2 activation, we have a number of clearly beneficial Nrf2 activators that can be implemented for nearly everyone while others should be used more discriminately. For example, low inflammatory diets and exercise were associated with high Nrf2 activity and are appropriate for practically everyone (Pall 2015). Incorporating foods that contain curcumin (from turmeric), sulfurophane (broccoli), vitamin D, and Omega 3s all show Nrf2 benefits.

In our patients with active inflammatory conditions, adding supplements to these food emphases can lower the ongoing damage and relieve many of the symptoms experienced. We can use individual ingredient supplements or combinations targeting Nrf2. Nrf2 Accelerator is one of the combination products we use, but many good ones are out on the market, such as the supplement produced by Protandim. Individual options include curcumin, sulforaphane (in Broccomax or Brocco-Protect), resveratrol, EGCG (green tea extract), quercetin, melatonin, vitamin E, luteolin, alpha lipoic acid, and many others. We can choose these products when their symptom relief benefits fit the given patient as well as addressing the Nrf2 pathway. In addition to these supplements, ketogenic diets may be appropriate Nrf2 therapy in some patients.

Helping patients restore or maintain healthier, more abundant lives requires understanding how our systems function, including Nrf2 and how we can modify its activity. Listening to our bodies as they tell us what is happening inside us and knowing how to respond is important for such healthier lives. We find many patients benefiting from these Nrf2 modifying therapies in our practice.

Exercise and Diet:

Pall, Martin L, and Stephen Levine. “Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors.” Sheng li xue bao : [Acta physiologica Sinica] vol. 67,1 (2015): 1-18.

Sulforaphane and others:

Houghton, Christine A et al. “Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician’s Expectation Be Matched by the Reality?.” Oxidative medicine and cellular longevity vol. 2016 (2016): 7857186. doi:10.1155/2016/7857186

Resveratrol and others:

Frontiers in Psychiatry. Nrf2 Activators as Dietary Phytochemicals Against Oxidative Stress, Inflammation, and Mitochondrial Dysfunction in Autism Spectrum Disorders: A Systematic Review.

Supplement research:

Robledinos-Antón, Natalia et al. “Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development.” Oxidative medicine and cellular longevity vol. 2019 9372182. 14 Jul. 2019, doi:10.1155/2019/9372182

Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.