How the Nrf2 System Protects Me

March 19, 2023

How Does the Nrf2 System Protect Me

The Nrf2 system (nuclear factor erythroid 2–related factor 2) is your master switch that turns on some 2,000 genes that help you turn off oxidative stress. The Nrf2 system also activates a whole portfolio of longevity genes. Last week, we learned that oxidative stress is the result of reactive oxygen species, escaping overworked mitochondria and damaging cell membranes. This week, we add the longevity mechanisms.

Nrf2 declines with aging, which appears to be inevitable and its overt causes are elusive. There are a lot of diseases associated with aging. Hence, knowing how Nrf2 interacts with those diseases will give us more tools to get to the root cause and either outright reverse them or soften the blow.

There are 9 standard hallmarks of aging: genomic Instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. An international meeting in Copenhagen just added 5 more. Of those first 9, the Nrf2 system modulates them all dramatically.

For example, Genomic Instability. As we age the lack of DNA repair leads to increased mutations and replication errors, which leads to cancer and cognitive decline. Nrf2 targets genes that lead to improved DNA repair. It's that simple. The key switch to fixing broken DNA is your Nrf2 system.

How about Telomere Attrition? Cells die when their telomeres get too short. Telomeres are the DNA caps on the end of your chromosomes. With each cell cycle, you lose a tiny bit of your telomeres. The Hayflick limit predicts you live only as long as your telomeres. But an enzyme will lengthen your telomeres, cheating the Grim Reaper. It's called TERT or Telomere Reverse Transcriptase. And what does Nrf2 have to do with TERT? Apparently everything. Re-lengthening your telomeres is one of antiageing's "Holy Grails".

Then there are Epigenetic Alterations. Our epigenome is composed of some 20 million markers on our chromosomes that regulate when we turn genes on and off. Those alterations are key to the development of cancers. Again, Nrf2 is key to the whole process of keeping that labeling and marking system stable.

Loss of Proteostasis is basically the accumulation of misfolded proteins. When our proteins are assembled and folded improperly, cells don't function well. Nrf2 actives genes, POMP and the PMSA family in particular, that regulate folding and misfolding. Examples of misfolded proteins include amyloid in Alzheimer's and Alpha-synuclein in Parkinson's.

Get the drift? Virtually every element of our 9 standard "Hallmarks of Aging" are intimately tied to Nrf2 and its appropriate activation. If you want to do a deeper dive: here are just a few of the thousands of research articles detailing that story.

Dysregulated Nutrient Sensing: FASEB, Antiox and Redox,

Mitochondrial Dysfunction: Current Opin Toxic.,

Cellular Senescence: Mol Chem Biochem,

Stem Cell Exhaustion: Frontiers,

Altered Intercellular Communication: Exercise Sport Sci Review, Biochem Pharm.,

It makes sense. If we are to maintain a healthy body, we need a switch that turns on that vitality across the board. Parsing down to the details, that switch, the Nrf2 system, plays a key role in the initiation and promulgation of each of the identified components.

www.What will Work for me? I had no idea about the breadth and depth of the Nrf2 science. In 2010 there were some 400-500 references in Pubmed. Now there are some 10,000 a year and what used to be thought of as a 3 to 4-step process is now much more complex with several hundred interlocking enzymes and interdependent steps. That makes it central to the treatment of just about every disease. Ok, really! Every disease. Next week, the evidence for that and how to treat it.

References: CellCell, Free Radical Biol Med, Nucleic Acid Res, Cell Death Dis, MDPI, Redox Biology, FASEB, Curr Opin Tox, Mol Chem Biochem, Frontiers, Exer Sport Sci Review, Biochem Pharma,

Pop Quiz

1. After 40, it's just patch, patch, patch! Why?                         Answer: Decline in the Nrf2 pathway.

2. Current research focuses on how many hallmarks of aging?                         Answer: The easy answer is 9 well-known ones but there have been recent additions. The story may not be over yet.

3. Can you name a few?                          Answer: genomic Instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. You get an A if you could remember 2.

4. Current research in Nrf2 is dramatically falling off as researchers focus on other things. T or F.               Answer: False. This is just about the hottest topic in town.

5. How many genes are known to be involved with the Nrf2 system?                      Answer: At least 2000 so far.