Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors.
An excellent question “so, what is Nrf2 and what does it do for us?” can be partly answered by the authors: They state “Nrf2” is a transcription factor (aka nuclear factor erythroid-2-related factor 2) which activates the transcription of over 500 human genes. Most of these genes have cytoprotective functions through mechanisms such as: Detoxification mechanisms and excretion of both organic xenobiotics and toxic metals; Increasing antioxidant activities; anti-inflammatory stimulation; mitochondrial function improvement and biogenesis; and stimulating autophagy via removal of cellular debris and dysfunctional organelles.
Nutrients with positive effect and related factors act to some degree by raising Nrf2 include as stated by the authors: “some phenolic antioxidants; gamma- and delta-tocopherols and tocotrienols; long chain omega-3 fatty acids DHA and EPA; many carotenoids of which lycopene may be the most active; isothiocyanates from cruciferous vegetables; sulfur compounds from allium vegetables; terpenoids.”
Other health promoting, Nrf2 raising factors include normal levels of hormesis creating oxidative stress, exercise and caloric restriction. The authors also note that increasing Nrf2 “has been found to prevent and/or treat a large number of chronic inflammatory diseases in animal models and/or humans including various cardiovascular diseases, kidney diseases, lung diseases, diseases of toxic liver damage, cancer (prevention), diabetes/metabolic syndrome/obesity, sepsis, autoimmune diseases, inflammatory bowel disease, HIV/AIDS and epilepsy. Lesser evidence suggests that raising Nrf2 may lower 16 other diseases. Many of these diseases are probable NO/ONOO− cycle diseases and Nrf2 lowers effects of NO/ONOO− cycle elements.”
Practice Implications:
It seems like forever ago… but it wasn’t that long ago in medicine that the mention of cytokines in a clinical paper was limited or absent. It also was not that long ago that many of these cytokines were either discovered or their function elucidated. Now it is completely common to see such things in the title of a paper and shows the rapid progression of medical thought in my opinion. Nrf2 is just such a factor which is critical to human health and affected by multiple natural agents and behaviors such as diet, lifestyle and related hygienic factors. As we see with many such regulatory factors in the human body it is supportive to the tenets of natural medicine that Nrf2 is mainly promoted by healthy diet and lifestyle factors.
Below I will summarize some of the conclusions regarding the connection with healthy habits, natural medicines and Nrf2
Food sources of specific nutrients are reported in this paper to promote Nrf2. These include the omega-3 fatty acids DHA and EPA which of course are associated with many other health benefits as well. In addition to fatty acids many carotenoids including lycopene (which may be the most active). In addition to these factors foods high in isothiocyanates from cruciferous vegetables and sulfur compounds from allium vegetables also are able to raise Nrf2 activity.
For years we in natural medicine have promoted the idea of “eating foods that nature makes attractive” such as colorful and aromatic foods. Our idea has been that the foods most attractive may have many health promoting nutritional factors. For a long time we considered things such as vitamin and mineral content likely the highest in this category, but with more modern understanding we know that other chemical factors in foods add greatly to the health and nutrient benefits of “attractive” foods”. A short list of the foods / spices and aromatics (often used in natural medicines) with some of the Nrf2 promoting factors include: eucalyptus, the flavors of cinnamon, cloves, and ginger, the yellow color in sunflowers, and the red color in tomatoes. Well-known terpenoids include citral, menthol, camphor, salvinorin A in the plant Salvia divinorum, the cannabinoids found in cannabis, ginkgolide and bilobalide found in Ginkgo biloba, and the curcuminoids found in turmeric and mustard seed.
A final key component to promoting the healthy benefits of Nrf2 function includes a topic I wrote about in the February-March issue of this review “ReDox –Our ever evolving understanding of oxidative balance, kinetics and implications in health and disease.” The idea being that the oxidation reduction cycles in the body never stop and without them we cannot maintain basic health and cell repair. While the authors do give a broader treatment to the relationship of ReDox to Nrf2, if the concepts are unclear the 2015 review I wrote will add some background. Essentially Nrf2 raising factors include normal levels of hormesis creating oxidative stress, exercise and caloric restriction. In other words “life” happening (if in a healthy body) is also promoting to Nrf2 and many other positive factors.
In their conclusion the authors sum up the major (and in my opinion clinically relevant) take home points from their review:
“While it is a major mistake to ignore the other Nrf2 cytoprotective mechanisms, it is also a major mistake to ignore the compelling evidence that the Nrf2 studies give us on the importance of enzymatic antioxidant mechanisms.
This paper started out emphasizing the special importance of Nrf2 to the hundreds of millions of people around the world who are exposed on a daily basis to toxic chemicals. The role of Nrf2 in producing complex and well coordinated detoxification mechanisms allows us to focus on raising Nrf2 as a way of substantially lowering the pathophysiological effects of such exposures by detoxification of the body, lowering levels of both organic, carbon-containing xenobiotic toxicants and also toxic metals.”
At the least this data review supports many of the healthy diet and lifestyle suggestions many of us have been making for years. In the broader sense it also elucidates a deeper understanding of the interplay of Nrf2, the immune system, human physiology and how we live. All of this supports healthy lifestyle, diet and natural approaches to medicine.