Longevity 1 – NRF2

NRF2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. NRF2 (nuclear factor erythroid-2-related factor 2) is a transcription factor that activates over 500 genes via molecules called sirtuins. NRF2 activation.

Recent research has identified certain processes to be very effective at stimulating our body’s natural mechanisms for creating antioxidants through a process called NRF2 activation. NRF2 (nuclear factor erythroid-2-related factor 2) is a transcription factor that activates over 500 genes via molecules called sirtuins. NRF2 activation can be achieved through exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF2 activators. Common NRF2 activators include curcumin (from turmeric spice – probably the best studied and most potent NRF2 activator), along with resveratol (from grapes), quercitin (from onions) and sulphoraphane (from broccoli) followed by antioxidants found in green tea and other sources. Different nutrients may activate NRF2 by different mechanisms and, when taken together, may be synergistic, or more effective when taken separately.

Supplementing with NRF2 activators is believed to offer a number of remarkable health benefits, from reducing inflammation and pain to protection against diabetes (reducing insulin resistance) and protection against a variety of degenerative and immune-based diseases.

“Activation of Nrf2 creates a downstream production of proteins and antioxidant enzymes, which provide benefits beyond direct-acting antioxidants.”

Benefits for human health

Oxidative stress and inflammation contribute to a large number of chronic diseases, including atherosclerosis, inflammatory bowel disease (IBD), rheumatoid arthritis, cancer, diabetes, obesity, metabolic syndrome, and many more. Although the pathology of each of these diseases is different, Nrf2 plays a role in many of them.

It is considered a major protective factor against these oxidative stress-related conditions.

Thus, Nrf2 activation or inhibition responding to cellular oxidative and electrophilic stress, and designed to restore redox homeostasis, paves a new way to understand, prevent, or even cure these complex diseases.

While oxidative stress activates Nrf2, researchers have looked for other ways to induce this protein for human benefit. Interestingly, there are a large number of Nrf2 activators in foods and dietary supplements, and even in lifestyle choices.


Activation of NRF2 is believed to provide many health benefits including:

  1. Reducing systemic inflammation
  2. Lowering of oxidative stress (reducing cellular DNA, RNA and protein damage)
  3. Improving mitochondrial function (cellular energy production)


Consuming fruits and vegetables not only meets nutritional needs but also provides a rich source of antioxidants.[7] However, extensive preclinical research now demonstrates that many phytochemicals in foods and supplements also regulate Nrf2; thereby increasing intrinsic and longer-lasting antioxidant support.[8] These include:

  • astaxanthin (from algae, fish and yeast)
  • blueberry
  • catechins (from tea, cocoa, legumes and grapes)
  • coffee
  • curcumin (from turmeric)
  • ellagic acid (from berries, fruit and nuts)
  • garlic
  • ginger
  • herb extracts from: milk thistle, cinnamon, rosemary, fennel, ginseng, schisandra, magnolia
  • isoflavones (from legumes)
  • kiwi fruit
  • naringenin (from citrus)
  • nutrients: vitamin D, zinc, chromium and arginine
  • pomegranate
  • purple sweet potato
  • resveratrol (from grapes, peanuts and berries)
  • sulforaphane (from cruciferous vegetables)
  • whey protein

The most well-known and widely used nutritional Nrf2 activators are sulforaphane, resveratrol and curcumin. Plan physical activities AKA exercise and IF activate NRF2 as well.

Role of Nrf2 in Oxidative Stress and Toxicity

Toxicology and Molecular Biology

Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia 26505


Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body’s needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol–based redox signaling. The nuclear factor erythroid 2–related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.


Since it was discovered as the transcription factor to mediate induction of ARE-dependent DMEs over a decade ago, Nrf2 has quickly emerged as a major regulator of oxidant resistance and has been implicated in a range of toxicities and chronic diseases that are characteristically associated with oxidative stress. Nrf2 is activated through a Keap1-dependent, evolutionarily conserved, dedepression signaling mechanism, wherein Nrf2 is suppressed under a basal condition through Keap1-controlled ubiquitination-proteasomal degradation and is activated by oxidants and electrophiles via modification of critical cysteine thiols of Keap1 and Nrf2. Activated Nrf2 mediates induced expression of an array of enzymes and signaling proteins to regulate drug metabolism, antioxidant defense, and oxidant signaling, thereby influencing oxidant physiology and pathology. By regulating oxidant levels and oxidant signaling, Nrf2 participates in the control of several programmatic functions, such as autophagy, inflammasome signaling, UPR, apoptosis, mitochondrial biogenesis, and stem cell regulation. Nrf2 exhibits multiple protective effects against toxicity and chronic disease naturally or through pharmacological means, opening new avenues for drug development. The protective capacity of Nrf2 could be hijacked by cancer cells to promote cancer growth and drug resistance, triggering potential side effects of ARE inducers but, at the same time, raising a possibility of developing Nrf2 inhibitors to treat, through personalized medicine, cancers that have elevated Nrf2 activities.

Link: https://www.annualreviews.org/doi/full/10.1146/annurev-pharmtox-011112-140320?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

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