The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body combats oxidative stress and gets rid of toxins.
I like to think of Nrf2 as flipping the switch that calls up the phase II enzymes to take out the trash produced in the first phase of detoxification. Nrf2 is also important in clearing out the free radicals produced in cells as part of their normal production of energy.
Your body’s antioxidant defense:
Nrf2 activates your body’s natural antioxidant defense system to reduce oxidative stress in the cell.
Specifically, the Nrf2 signaling pathway can increase the production of GSTs, NQO1, UGTs, and SULTs. These are the body’s natural antioxidant defense systems, important in every cell, all the time — but especially important when your body is under stress from an increased toxic burden.
Chronic oxidative stress is part of the root cause of chronic diseases; thus, activating the Nrf2 pathway is thought to reduce disease risk for quite a few chronic conditions.
The Nrf2 pathway is important for protecting against:[ref]
- autoimmune conditions
- respiratory problems
- digestive issues
- cardiovascular disease
- metabolic diseases
- neurodegenerative diseases
How does Nrf2 work?
Normally, Nrf2 is located in the cytosol of the cell. It is hanging out, waiting to be needed.
When oxidative stress levels in a cell increase, Nrf2 moves into the cell nucleus, where the DNA is located. There it is able to bind to certain areas of the DNA to cause the cell to produce the innate antioxidants needed to decrease the oxidative stress in the cell.[ref]
What is oxidative stress?
Oxidative stress in a cell is the imbalance between reactive oxygen species (ROS) and the cell’s antioxidant capability.
Too much ROS puts the cell in a state of oxidative stress, which means that damage can occur due to the excess of free radicals. This damage can take the form of damaged proteins, oxidized lipids, or mutations or breaks in the nuclear DNA.[ref]
Reactive oxygen species form in cells due to normal cellular processes, and your cells then balance this out with antioxidants.
The problems come when cells are exposed to environmental toxicants or other stressors that increase ROS. Sources of oxidative stress include radiation, environmental pollutants, carcinogens, and cigarette smoke.
We are all exposed to environmental toxicants daily, from air pollution, food additives, microplastics, and personal care products.
Which genes does Nrf2 activate?
Normally, Nrf2 is present in the cytosol of cells and kept there by another protein (called Keap1). These two molecules hang out together while normal cellular processes take place.
When oxidative stress is high in cells, Nrf2 disassociates from Keap1 and moves to the nucleus. In the nucleus, Nrf2 turns on certain genes for transcription.
Nrf2 can activate the GST (glutathione S-transferase) genes in order to eliminate toxic compounds and reduce oxidative stress.[ref]
Related article: See your GST genetic variants
NRF2 can also induce UGT1A1 and UGT1A6, which are important for making certain toxins, such as acetaminophen, more water-soluble for excretion.
Related article: See your UGT genetic variants
Nrf2 modulates inflammation:
In addition to activating genes that counter oxidative stress, Nrf2 also keeps inflammatory molecules in check. NF-κB is an important regulator protein in the immune system. When NF-κB is not correctly regulated, the immune response can be overactive, such as in septic shock or autoimmune diseases.
Nrf2 acts to keep NF-κB in balance. Both molecules act in the nucleus to turn on other genes, and they interact to balance out proinflammatory and antioxidant responses.[ref]
Nrf2: Genotype Report
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Variants in the NFE2L2 (Nrf2) gene are fairly common. Some variants increase Nrf2 pathway signaling, and some diminish it. Research on these variants includes impacts on cancer prognosis, lung volume in smokers, and Parkinson’s disease relative risk.
A genetically increased Nrf2 pathway is associated with a decreased mortality risk in smokers, likely due to the body’s upregulated antioxidant defense protecting against the cellular damage from cigarettes.[ref]
Genetic variants that increase Nrf2 (generally a good thing!):
Check your genetic data for rs6726395 (23andMe v4; AncestryDNA):
- G/G: greater lung volume in smokers[ref], decreased risk of AMD (age-related macular degeneration)[ref], increased Nrf2
- A/G: somewhat greater lung volume in smokers, increased Nrf2
- A/A: typical
Members: Your genotype for rs6726395 is —.
Check your genetic data for rs13001694 (23andMe v5; AncestryDNA):
- G/G: reduced risk of all-cause mortality, especially in smokers[ref], increased Nrf2
- A/G: reduced risk of all-cause mortality, especially in smokers; increased Nrf2
- A/A: typical
Members: Your genotype for rs13001694 is —.
Check your genetic data for rs1806649 (23andMe v4):
- C/C: typical
- C/T: significantly reduced risk of death from COPD; increased Nrf2
- T/T: significantly reduced risk of death from COPD (70% reduction)[ref]; increased Nrf2
Members: Your genotype for rs1806649 is —.
A genetic variant that reduces Nrf2 expression:
Check your genetic data for rs6721961 (23andMe v4; AncestryDNA):
- G/G: typical
- G/T: typical
- T/T: significantly diminished Nrf2 expression, increased risk of lung cancer[ref]
Members: Your genotype for rs6721961 is —.
If you don’t have the variants that increase Nrf2 – or if you are exposed to environmental toxicants – you may want to look at ways to increase your Nrf2 levels.
Increase Nrf2 through lifestyle changes:
Regular exercise upregulates the Nrf2 pathway.[ref] This is a free and easy lifehack – and one more reason to get outside and get active today.
Nrf2 Activators: Supplements that extend Nrf2
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Originally published: June, 2015
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.