Nrf2 - The Most Important Signaling Pathway In The Body?

Nrf2 - The Most Important Signaling Pathway In The Body?

This article is an excerpt from out forth-coming big new book, the Resilient Being and more specifically, from its Contextual Resilience chapter.

Nrf2 (nuclear factor erythroid-derived 2 like protein) is a transcription factor commonly found in a cell’s cytoplasm. It activates the transcription of over 500 genes in the human genome. When Nrf2 is activated it goes into the nucleus to perform its main functions.  It binds to the antioxidant response elements (ARE) located in the promoter region of genes encoding many phase II detoxifying or antioxidant enzymes and related stress-responsive proteins.

Image source: Northwest life Science Specialties.

Under normal conditions, Nrf2 is repressed by Keap1, which is an adaptor protein for the degradation of Nrf2. But during oxidative stress, Nrf2 is derepressed (or activated) and this activates the transcription of protective genes. The Keap1-Nrf2 system plays a role in inflammation-associated pathogenesis.

The Nrf2 signaling pathway and its subsequent induction of cytoprotective (protection of cells from harmful agents) protein expression is the main cellular defense mechanism against oxidative and electrophilic stress. Therefore, interactions of Nrf2 with other signaling components regulate the efficiency of the cellular stress response. One of these is autophagy (read a comprehensive article on autophagy here).

The health benefits of Nrf2 are for example:

Lifestyle factors that activate Nrf2

Lifestyle and other factors activating Nrf2 include heat and cold exposure  – when practiced in one session as heat alteration may produce the best results (see a specific article on Heat Alteration). Physical exercise is also a known Nrf2 activator. For example acute aerobic exercise elicits activation of nuclear Nrf2, regardless of exercise intensity. But higher-intensity exercise results in greater activity of glutathione reductase.

Nrf2 signaling in sedentary older adults can also be restored to a degree with moderate exercise training. To conclude, episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, it leads to upregulation of endogenous antioxidant defenses and overall greater ability to fight oxidative stress.

Other lifestyle factors increasing Nrf2 include fasting, calorie restriction, and the activation of ketosis (check Biohacker's Guide to Ketosis here). It should be also mentioned that well functioning mitochondria also almost automatically means a well-functioning Nrf2 signaling. It is also known that loss of Nrf2 leads to impaired mitochondrial function.

Nutritional factors supporting Nrf2

There are multiple nutritional compounds and components that support the function and activation of Nrf2. Several natural antioxidants have emerged as possible Nrf2 pathway activators amongst which chalcones are very active ones. Chalcones constitute an important group of natural compounds that are especially abundant in fruits (e.g., citruses, apples), vegetables (e.g., tomatoes, shallots, bean sprouts, potatoes) and various plants and spices (e.g., licorice),—many of which have been used for centuries in traditional herbal medicine. They activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins.

Image: Multi-target interaction of chalcones on cross-talk between Nrf2 and NF-κB response pathways involved in inflammation.

Source: de Freitas Silva, M. et al. (2018). The Keap1/Nrf2-ARE pathway as a pharmacological target for chalcones. Molecules 23 (7): 1803.

Chalcone compound

Sources

Trans-chalcone 

A flavonoid precursor

Xanthohumol

Humulus lupulus or Hops

Licochalcone E 

Licorice root

Safflor Yellow A

Various yellow colored foods

Lophirones B & C

Lophira lanceolata or dwarf red ironwood

Isoliquiritin 

Licorice root

Isoliquiritigenin

Licorice root

Isosalipurposide 

Helichrysum arenarium or dwarf everlast flowers

Naringenin 

Various foods such as cocoa, Greek oregano, sour orange, grapefruit etc.

Cardamonin 

Alpinia katsumadai & Alpinia conchigera

Butein 

Various plants such as Butea dahlia, Coreopsis and Searsia

HMC (Hesperidin methyl chalcone)

Citrus fruits, especially in their peels, such as orange peels

Flawokawains A, B & C

Piper methysticum (Kava-kava)

 

Image: Main polyphenol family members.

Source: Orlikova, B. & Tasdemir, D. & Golais, F. & Dicato, M. & Diederich, M. (2011). Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes & Nutrition 6 (2): 125–147.

Flavonoids can be further divided into various subclasses of which chalcones, flavonols, flavones, flavanones, anthocyanidins, and isoflavonoids are the most common. See a comprehensive list of flavonoids in Biohacker’s Handbook’s Nutrition Chapter.

Other foods and compounds that are known to activate Nrf2:

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Have you heard of Nrf2 before? What did you learn reading this article? Tell us in the comments!

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Laura

Laura

I am forever grateful for Nrf2 activation!! I have been taking an Nrf2 activator for almost 8 years now!! More potent than any single ingredient like resveritrol, silymarin, or turmeric it’s is a synergistic compound with loads of published science behind it!! Everyone needs to know about this!! Thanks for sharing

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