Nrf2 and Oxidative Stress

March 11, 2023

Nrf2 System and Oxidative Stress

No, we are not talking about Nerf Balls or Smurfs. The Nrf2 (nuclear factor erythroid 2–related factor 2) system is right up with Nitric Oxide in importance in that it plays a key regulatory role in managing oxidative stress. Oxidative stress is one of the key drivers of getting old and falling apart. That makes understanding it important. Hence, here starts a series to explain it.

First, what is oxidative stress? It is the unbalanced environment where too many oxidizing compounds, "reactive oxygen species", overwhelm your natural antioxidant control systems. Our mitochondria are delicately balanced furnaces and when too many nutrients get shoved in from all directions. extra electrons slip away and glom onto an oxygen molecule, making O2-. It's biochemically impossible to hang onto every electron because of their very nature being a part-time particle and a part-time wave. That O2- is the superoxide anion that is chemically very dangerous. It can degrade membranes and proteins all over the place. If we have enough of the enzyme SOD, superoxide dismutase, we can neutralize it by making H2O2, peroxide. Peroxide is no angel but at least it's not negatively charged. If we have enough glutathione, we can turn peroxide into water. In our brains, our plasmalogen molecules soak up peroxide, becoming the first line of defense in the brain against peroxide. Our plasmalogens decline, synapses disappear, brains shrink and cognitive decline follows.

If we don't have SOD, the O2- molecule may interact with Nitric Oxide and make an ONOO- molecule, peroxynitrite, which is another demon. To round out the BIG 4, peroxide, in the absence of sufficient glutathione or catalase, with react with iron to make OH-, the hydroxyl radical. Glutathione or catalase are two protective "antioxidants" that convert H2O2 to water and oxygen.

There you have it: the Big 4 of oxidative stress, O2-, ONOO-, H2O2, and OH1. They are constantly being made at a low level and being cleaned up. Our immune system uses some of them quite creatively to help kill viruses and invading bugs. It's all in the balance. Too many and you damage just about every pathway that leads to all diseases and aging. Name any disease of aging and you will see oxidative stress as tipping the balance towards having more of it.

Here is the rub. We haven't been very effective at turning oxidative stress off with the oral antioxidant supplement approach. There are foods that help a little, but not at the level needed to dramatically turn on sufficient response.

This is where Nrf2 comes in. Nrf2 is a transcriptional protein that turns on some 2000 genes, all of which combine to turn off oxidative stress. It upregulates the production of more catalase, more glutathione, more superoxide dismutase, the Big 3 internal antioxidants. The Nrf2 system is critical for cell survival in times of oxidative stress.

That's why we need to know about NRF 2 and choose a lifestyle of protecting it. Unfortunately, Nrf2 declines with age. As Hamlet said, "Therein lies the rub". Step one is knowledge. Next week, step two.

www.What will Work for me? I've been pushing anti-oxidants and encouraging all sorts of behaviors to change the course of disease, sometimes to little effect. That has been discouraging to all of us. Gamma, delta tocotrienols, fish oil, turmeric,....on and on and we haven't gotten much return on investment. The Nrf2 system is the controller of your antioxidant response. That's the upstream effect we need to focus on.

References: Wikipedia, MDPI, Science Direct, Wikipedia, Oxid Med Cell Long, Pharnacogn Review, Free Rad Biol Med, Free Radic Bio Med, PlanSponsor, Annual Review Pharm Toxic, Foods,

Pop Quiz

1. What is Nrf2?                                    Answer: nuclear factor erythroid 2–related factor 2 . Stick with Nrf2. It is the primary nexus of your metabolic response to oxidate stress.

2. What is oxidative stress?                           Answer: the imbalance to too many reactive oxygen species driven mostly by loose electrons escaping "overly heated" or damaged mitochondria. "Overheating" of mitochondria is mostly driven by forcing too many carbohydrates and fats into the intake funnel of the mitochondria (Think Thanksgiving Dinner....or even a double burger, fries, and milkshake). They just get overwhelmed and don't have sufficient places to send electrons to. Electrons escape...and you are off to the races. Damage to the lipids of cells sets off more inflammation.


3. Can you name the Four Dark Horsemen of Oxidative Stress?                        Answer: Reactive oxygen species.  O2-, ONOO-, peroxide (H2O2), and OH-. 

4. What does the NRF2 system do to balance that stress?                            Answer: The Nrf2 system is a transcriptional protein that turns on some 2000 genes, all of which shift you to making the BIG 3 internal "anti-oxidants": glutathione, catalase, and superoxide-dismutase. They work mostly by neutralizing the common pathway of oxidate stress, excess hydrogen peroxide.

5. What happens to the Nef-2 system as you age? Answer: it declines. Bummer. But wait, we can help fix that. Tune in next week.

6.  What's a "rub", as per Hamlet?               Answer: a figure of speech from the Elizabethan era using a bump or obstruction on a lawn-bowling fairway that changes the direction of the ball....hence, something that unexpectedly changes your intended course of action.