Supporting Science
Nrf2 evolved in the earliest oxygen-breathing animals
Nrf2 originated in the earliest oxygen-breathing animals, long before humans.
The Nf2 Cell Defense Pathway first appeared in early animals around 500 millions years ago – at the time when atmospheric oxygen levels began to rise (1). Of course, oxygen is essential for animal life, but it also generates harmful chemicals — reactive oxygen species and free radicals that damage DNA, proteins, lipids, cell mitochondria and ultimately injure nerves, joints, cartilage, skin, eyes, and all vital organs (2). The Nrf2 Cell Defense Pathway evolved in early animals to perceive and respond to the toxic threats of oxygen and provide protection to every cell and vital organ in the body (3, 4, 5). It also evolved to protect against a variety of environmental toxins including heavy metals like lead and arsenic (6).
The fact that the Nrf2 Cell Defense Pathway has persisted in all animals for millions of years testifies to its great importance. Not surprisingly, mice genetically engineered for Nrf2 deficiency exhibit more than 15 specific health disadvantages. To read about the many consequences of Nrf2 deficiency, see: Published Research/Consequences of Nrf2 Deficiency.
Components of the Nrf2 Cell Defense Pathway
Nrf2 is a transcription factor that drives gene expression by binding specific sequences in DNA. When activated, Nrf2 switches on the expression of more than 200 protective genes encoding anti-oxidant and detoxifying enzymes. These enzymes not only neutralize free radicals but also safely metabolize harmful chemicals that would otherwise aggravate oxidative damage (3, 7).
Activation of the Nrf2 Cell Defense Pathway is controlled by an important oxidative threat sensor that is designed to match Nrf2 function precisely to the level of oxidative stress. This threat sensor contains the Nrf2-binding protein Keap1 that sequesters Nrf2 in the cytosol, thereby controlling Nrf2 activation (3). With proper sensing of oxidative stress, Nrf2 is released from Keap1. Activated Nrf2 then rapidly moves to the cell nucleus to initiate gene expression.
The oxidative threat sensor requires special Nrf2 activators
Once activated by proper sensing of oxidative stress, Nrf2 binds to DNA to switch on the expression of over 200 protective genes that encode anti-oxidant and detoxifying enzymes.
The sensing mechanism that recognizes oxidative threats involves oxidation-sensitive sulfhydryl groups in Keap1. For this sensing mechanism to perceive oxidative stress accurately and activate Nrf2, small nutrient molecules known variously as Nrf2 "activators", "inducers", or "co-factors", are required (3, 8). An important feature of truly effective Nrf2 activators is "oxidation-reduction lability" that facilitates electron exchange between molecules (9). Without Nrf2 activators, the Nrf2 oxidative stress sensor is mostly blind, and oxidative stress and other chemical threats result in only very weak Nrf2 activation – approximately 10-20% of the full protective potential (8).
You must obtain Nrf2 activators from your diet
It is important to understand that your body can't make Nrf2 activators and that they must be obtained from your diet (8). Furthermore, only very few truly effective Nrf2 activators are found in nature. The simplest most potent ones are the alkyl catechols generated by bacteria that express an enzyme known as phenolic acid decarboxylase (PAD). Most PAD-expressing bacteria are found living on plants; and, consequently, they are also found in many traditionally fermented beverages, fruits, and vegetables (8, 10).
The other natural Nrf2 activators are curcumin from the Indian spice turmeric (11, 12) and sulforaphane which is found in cruciferous vegetables like broccoli (13, 14). Curcumin and sulforaphane are more complex molecules than the alkyl catechols generated by PAD-expressing bacteria, and this complexity likely interferes with their absorption and bioavailability (15, 16). In contrast, the simple structure of the aklyl catechols favors absorption. Also, in laboratory assays, the aklyl catechols are comparable to or even more active than curcumin and sulforaphane at activating Nrf2 (8, 11).
Latarum® expresses PAD and generates a potent Nrf2 activator
Latarum® probiotic has been selected for PAD expression from a natural strain of plant bacteria called Lactobacillus plantarum. The PAD in Latarum® generates an alkyl catechol. known as 4-vinyl catechol that potently activates Nrf2 (8). It generates 4-vinyl catechol from caffeic acid, by removing a carboxyl group. Coffee and apples are particularly rich sources of caffeic acid (17), and that's why Latarum® probiotic should be combined with a daily diet containing coffee and/or apple products. (Note: caffeic acid and caffeine are not related).
Latarum® probiotic excises an important Nrf2 activator from caffeic acid, using an enzyme known as phenolic acid decarboxylase (PAD). Humans, other animals, and even most bacteria can't make this important enzyme.
Latarum® is regularly tested for conversion of caffeic acid to 4-vinyl catechol. This distinction is important because not all strains labeled "Lactobacillus plantarum" express the necessary PAD enzyme. Neither do the majority of bacterial strains, including a variety of other Lactobacillus species such as Lactobacillus acidophilus and Lactobacillus paracasei from yogurt (8).
Coffee and apples are rich sources of caffeic acid that Latarum® converts to 4-vinyl catechol, a potent Nrf2 activator that supports the Nrf2 oxidative stress sensor.
When you take Latarum® probiotic twice per day, in combination with a daily diet that consistently includes coffee and/or apple products, you provide your digestive tract with sources of PAD enzyme and caffeic acid that can generate a steady supply of Nrf2 activator. With this simple strategy, you can restore the protective power of your Nrf2 Cell Defense Pathway to its full potential. And with your Nrf2 functioning again, you can get healthier, feel better, experience improved vitality, and prevent premature aging.*
Click on numbers in parentheses for links to supporting research publications.
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
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