Why NRF2 Activation Can Make You More Sick — MyBioHack

Hormesis

NRF2 needs to be hormetically activated to have its benefits.

That means that you shouldn't activate it every second or every day, so it is a good idea to take breaks from it (ie 5 days on 5 days off or every other day).

NRF2 also needs to meet a certain threshold to activate its hormetic response, so too little of a stressor may not activate it. 

DJ-1 Oxidation

Protein deglycase DJ-1 (DJ-1), also known as Parkinson disease protein 7 (PARK7) is a master regulator and sensor of redox status. R

DJ-1 is important for regulating how long NRF2 is available to do its job and create an antioxidant response. R R

If DJ-1 gets overoxidized, then there is less DJ-1 protein available. R

This causes NRF2 activity to die too quickly (see post on DJ-1) as DJ-1 is paramount for keeping NRF2 from being broken down in the cell and allows levels of NRF2 to accumulate. R R 

If DJ-1 protein is non-existent or overoxidized, then NRF2 expression will be minimal, even with DIM or other NRF2 activators. 

Proper DJ-1 expression is necessary to restore impaired NRF2 activity. R

Read more about DJ-1 here and how to fix its expression.

Chronically Sick With Infections And Metals

Also, you are chronically sick (ie CIRS, chronic infections/dysbiosis/SIBO, heavy metals like mercury built up, root canals) then these can block the systems of NRF2 and phase 2 detoxification.

Instead of oxidative stress turning NRF2 into an antioxidant, NRF2 doesn't become cleaved and the original oxidative stress hangs around and damages the cell - there is no antioxidant reaction.

This a major reason why many people who have CIRS have multiple sensitivities and react to everything.

Some may think that when they take something they are having a herx reaction (herx may be bullshit), but in response you are just damaging your body further.

Once you fix the underlying infection (ie binders such as cholestyramine for CIRS or chlorella/clay for mercury) and allow the liver to properly release toxins into the bile to be fully excreted, then slowly build up the hormetic reaction of NRF2 activation.

If the bile is still toxic and doesn't go out of the body it will reactivate NRF2's oxidative stress and make you feel worse when you reabsorb it in the GI tract. R

This is because lipophilic (fat soluble) toxins need to get converted into hydrophilic (water soluble) compounds before they are excreted.

A good example of this whole scenario is with Ochratoxin A, which can block NRF2 from working. R R R

So other than treating the underlying infection, histone deacetylase inhibitors may block the oxidative response from some of the things that cause NRF2 activation (but may also stop NRF2 from activating in general), which may be a double-edged sword.

DIM may also help if NRF2 is physically blocked. R 

Fish Oil (Cholinergic) Dysregulation

Cholinergics are anything that increase acetylcholine (ACh) or choline in the brain (via increasing ACh or inhibiting the breakdown of ACh). 

A lot of my clients with CIRS (as well as I) tend to have problems with dysregulation of acetylcholine levels in the body and brain. 

I used to have problems with fish oil, as some of my friends as well.

Fish oil activates NRF2, which is how its antioxidant response inside the cell works (works differently on the cell membrane). R

People with chronic infections or chemical sensitivities may have problems with oxidative stress and acetylcholine excitotoxicity (from organophosphate accumulation), which may make fish oil more inflammatory than beneficial. R R

Choline deficiency actually induces NRF2 as well, so eating a diet with some choline (eggs, blueberries, etc) may help mitigate the cholinergic dysregulation. R