What is Nrf2?

Our DNA encodes about 20,000 genes, each representing a “blueprint” for the production of a protein or enzyme necessary for a healthy existence.  Each of these “blueprints” requires a regulating control called a “promoter” that determines precisely how much of each product is produced, and under what circumstances.  By binding to one specific type of these switch-like promoter regions called the “Antioxidant Response Element (ARE)” the Nrf2 factor controls the rate of production from hundreds of different genes that allow cells to survive under stressful conditions.   These genes produce a large variety of antioxidant enzymes that create a network of protection by neutralizing primary and secondarily generated oxidants and by cleaning up the toxic byproducts they leave in their wake, as well as by helping to repair the damage  they have caused.

What is oxidative stress?

Oxidants such as the superoxide radical (O2-.) and hydrogen peroxide (H2O2) are produced by the process of “burning” the foods that sustain us, just as the internal combustion engines in our cars produce similar reactive chemicals.  Cars have catalytic converters to neutralize and detoxify these reactive chemicals; our bodies have antioxidant enzymes to accomplish the same result.  The Nrf2 pathway senses the need for these antioxidant enzymes and regulates their production to maintain metabolic balance.  Several things can upset this delicate balance, and simply growing older is one of them.  We produce less Nrf2 as we age, and the balance slowly tips toward the oxidative side—a condition known as “oxidative stress.”  Disease processes can also result in overproduction of oxidants.  Infections, allergies, and autoimmune diseases activate our immune cells, which produce reactive oxidants (O2-., H2O2, OH.  and HOCl) in order to kill germs that the immune system assumes to be present, but our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation.  Other major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants, creating oxidative stress, and inflammation.

What are Nrf2 activators?

The Nrf2 protein, known as a transcription factor because of its ability to control genes, is the key component of a pathway (a sequence of biochemical reactions in a cell) that senses and responds to changes in oxidative balance.  The sensing components of the pathway chemically modify and release Nrf2 (i.e., they activate it) so that it may diffuse into the nucleus of the cell where the DNA resides.  It can then “switch on” or “turn off” the genes it controls (often termed survival genes) to produce the protected state within the cell.  Fortunately, many of the chemical compounds that are Nrf2 activators are produced by certain plants, crude extracts of which were known to our ancestors centuries ago in traditional Chinese, Ayurveda, and Native American medicines.  These phytochemicals appear to be just as potent, and to have fewer (if any) side-effects, as the Nrf2-activating pharmaceutical products that are beginning to appear.

Why do we need Nrf2-activating supplements or therapeutics as we age?

Why should we be concerned with supplements or therapeutics that can adjust the Nrf2 pathway?  Isn’t it, after all, part of a very large network of interactive and self-regulating pathways that automatically adjust to achieve proper balance based upon our metabolism?  In a young healthy animal, this appears  to be the case.  In post-reproductive organisms, however, things begin to change, as Nrf2-activation capabilities decline with age.  As harsh as it may sound, after animals have passed on their DNA and reared their offspring they have mostly served their purpose as far as Mother Nature is concerned  While it may not be nice to fool Mother Nature, perhaps people can agree that it’s now acceptable to tinker a little with Mother Nature.

Many studies have shown that the concentration of Nrf2 in cells declines as animals age.  Old age brings with it increased markers of oxidative stress and an assortment of “age-related diseases” such as atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer’s and Parkinson’s diseases.  All of these diseases have been characterized by evidence of increased oxidative stress.  By gently stimulating our aging cells’ ability to activate and modulate Nrf2, we aim to restore and enhance our body’s own ability to counteract the effects of oxidative stress.

In our experience with human subjects, the level of plasma TBARS (thiobarbituric acid)—which is a measure of oxidative stress—have all declined to the Target Range of 1.0-1.5 μM (μM malondialdehyde equivalents) within a span of about a month.

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