Individual NRF2 Activators:
When considering the need, or at least the potential benefit, of taking a multi-vitamin supplement or other nutritional supplements on a daily or regular basis, one should ask first if they are already maintaining an ideal diet. If the answer is no, then the argument is established that there is at least a potential benefit. The question then becomes what supplements are best to provide nutrients that are most likely to be sub-optimal in your diet.
Based on current theories in nutrition, our diets should include plenty of vegetables (especially raw) and fruit. But most people probably do not get optimal amounts of the nutrients associated with these vegetables and fruits. These nutrients include vitamins, minerals, antioxidants and other nutrients. Vitamins and minerals are addressed elsewhere.
“Oxidative Stress” and Antioxidants
Current nutritional research supports the belief that many diseases, including diabetes, hypertension, cardiovascular diseases, obesity, liver disease, arthritis and some cancers, are a result of “Oxidative Stress.” Oxidative Stress is an over-abundance of reactive oxygen species (ROS), or “free radicals”, which are destructive molecules that are in our food, our environment and created by our cells during normal metabolic processes. ROS cause oxidation – or damage – to DNA, RNA, proteins and cells analogous to rust damaging steel. To combat these ROS, our cells have protective systems that manufacture antioxidants which neutralize ROS, but as we age there is a gradual impairment of these systems resulting in less antioxidant activity thus greater damage to our DNA, RNA and cells which impairs function and can lead to the above diseases.
Ever since Linus Pauling, science has turned to antioxidants to offset the damages of oxidative stress as a means of promoting health. Antioxidant supplements are widely recommended and their use is widespread. Studies have shown that diets high in natural antioxidants (such as the Mediterranean (anti-inflammatory) diet, Okinawan or Paleo diets) seem to provide protection against oxidative stress. Statistics suggest that populations following these diets have less degenerative disease and greater longevity.
Recent research has identified certain processes to be very effective at stimulating our body’s natural mechanisms for creating antioxidants through a process called NRF2 activation. NRF2 (nuclear factor erythroid-2-related factor 2) is a transcription factor that activates over 500 genes via molecules called sirtuins. NRF2 activation can be achieved through exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF2 activators. Common NRF2 activators include curcumin (from turmeric spice – probably the best studied and most potent NRF2 activator), along with resveratol (from grapes), quercitin (from onions) and sulphoraphane (from broccoli) followed by antioxidants found in green tea and other soures. Different nutrients may activate NRF2 by different mechanisms and, when taken together, may be synergistic, or more effective when taken separately.
Supplementing with NRF2 activators is believed to offer a number of remarkable health benefits, from reducing inflammation and pain to protection against diabetes (reducing insulin resistance) and protection against a variety of degenerative and immune-based diseases.
Because antioxidants and NRF2 activators are present naturally in many vegetables and fruits, when we eat these foods we reap the benefits.
But do we?
The truth is sometimes yes, sometimes no. When we cook plant foods, many antioxidants are destroyed, sometimes as much as 97%. Unfortunately, even when eaten raw the antioxidants in food are often poorly absorbed through the stomach or intestines. Even when they get absorbed into the blood, they often have poor penetration into cells, especially into the brain and nervous system. In many cases the antioxidants we ingest simply do not get to where they can do the most benefit: within the cells. In other words, nutrients in our food are sometimes not very bioavailable (not available to the cells that need them).
Over the last few years, science has developed new techniques to overcome the problem of bioavailability, including use of nanoformulations. Nanoformulations reduce the size of the nutrient particles down to tiny micron levels and sometimes attach the nutrient to a second component that allows for the particle to be much better absorbed. Studies have demonstrated that nanoforumulations such as “phytosomal curcumin” have improved absorption as much as 29 times more effective.
Microsizing and nanoformulations are revolutionizing the pharmaceutical industry by providing the means to allow medications and nutrients that are poorly absorbed to become effectively absorbable and bioavailable. Currently, NRF2 activators that have been nanoformulated include curcumin, quercitin, grape seed extract and green tea extract.
Benefits of NRF2 Activators
Recent research has found that “NRF2 activation” is very effective at stimulating our body’s natural protective mechanisms including promoting endogenous (natural) antioxidant production.
Activation of NRF2 is believed to provide many health benefits including:
- Reducing systemic inflammation
- Lowering of oxidative stress (reducing cellular DNA, RNA and protein damage)
- Improving mitochondrial function (cellular energy production)
NRFT2 activation may have a positive impact on chronic inflammation and oxidative stress and so may be useful in the prevention or treatment of many common chronic disease processes including obesity and high blood pressure and reducing the risk of diabetes, cardiovascular disease and stroke. NRF2 activators have been shown to protect the liver in conditions of chronic hepatitis and fatty liver.
NRFT2 activation and Pain
NRF2 activation is thought to reduce pain related to many conditions. The muscle pain and fatigue associated with fibromyalgia is believed to respond to NRF2 activation. NRFT2 activation may reduce the central sensitivity associated with many chronic pain conditions including chronic headaches, chronic back pain, fibromyalgia and interstitial cystitis. There is evidence that NRFT2 activation may reduce the development of opioid tolerance and opioid-induced hyperalgesia (increased pain thought to possibly arise from the use of opioids).
NRFT2 activation and Obesity
Obesity, once thought to simply be an overabundance of stored fat is now understood to reflect a much more serious condition characterized by increased systemic inflammation and oxidative stress. As a consequence, obesity is clearly understood to be a major contributor to the development of hypertension, heart disease, stroke and some cancers. Evidence is mounting that NRFT2 activation helps protect against these conditions.
NRFT2 Activation and Addiction
Many of the brain’s neurotransmitters and neurochemical processes are impaired in conditions of chemical and behavioral addiction. NRT2 activation may play a role in facilitating restoration of these neurochemical processes and facilitate addiction recovery.
How is NRF2 activation achieved?
NRF2 activation can be achieved through:
- Calorie restriction (including fasting)
- Ingestion of natural nutrients and certain antioxidants that are NRF2 activators
Common NRF2 activators include curcumin (from turmeric spice – probably the best studied and most potent NRF2 activator), along with resveratrol (from grapes), quercetin (from onions), sulphoraphane (from broccoli) as well as many antioxidants found in green tea and other soures such as raspberries, pomegranates and dark chocolate. Many of the beneficial effects of antioxidants are actually produced through the NRF2 regulatory response, rather than exclusively through direct antioxidant chemistry as previously believed.
Different nutrients may activate NRF2 by different mechanisms and when taken together may be synergistic, or more effective when taken together than when taken separately. NRF2 activators are also found in vegetables including brussel sprouts and garlic, and fruits such as blackberries, raspberries and pomegranates as well as red wine and dark chocolate.
Supplementing with NRF2 activators is believed to offer a number of potential health benefits, from reducing inflammation and pain to protection against diabetes (reducing insulin resistance) and protection against a variety of degenerative and immune-based diseases.
The following is a list of common NRF2 activators:
- Curcumin (found in turmeric)
- Resveratrol (found in grape skins and red wine)
- Pterostilbene (found in blueberries, cranberries and grapes)
- Silybin (found in milk thistle)
- Sulforphane (found in brocolli, brussels sprouts, cabbage, cauliflower, bok choy, kale, collards, and mustard)
- Alpha Lipoic Acid (found in red meat, organ meats (i.e. liver), and yeast, particularly brewer’s yeast)
- Vitamin D (found in egg yolks, saltwater fish, liver. and dairy products like milk)
Nanoformulations of NRF2 Activators:
- PolyResveratrol (a mixture of 6 NRF2 activators)
- Meriva (curcumin phytosome)
- Siliphos (silybin phytosome)
Palmitoylethanolamide (PEA), an endogenous fatty acid amide, is emerging as a novel agent in the treatment of pain and inflammation. Human studies demonstrate PEA benefits to include peripheral neuropathies such as diabetic neuropathy, chemotherapy-induced peripheral neuropathy, carpal tunnel syndrome, sciatic pain, osteoarthritis, low-back pain, failed back surgery syndrome, dental pain, central neuropathic pain in stroke and multiple sclerosis, chronic pelvic pain, postherpetic neuralgia, and rectal and vaginal pains. (see PEA)
Studies with these supplements offer significant health benefits – for more information, see individual links:
* These statements have not been evaluated by the Food and Drug Administration. This documentation is not intended to diagnose, treat, cure, or prevent any disease.
Listed below are many recently published research articles that explore the many potential benefits of supplementing with NRF2 activators. In addition to these articles are many links listed in the individual pages for each of the nutrients listed above.
NRF2 as Regulator – Overviews
- Natural product-derived pharmacological modulators of Nrf2:ARE pathway for chronic diseases. – PubMed – NCBI
- NRF2-regulation in brain health and disease – implication of cerebral inflammation – 2014
- Nrf2, a master regulator of detoxification and also antioxidant, anti- inflammatory and other cytoprotective mechanisms, is raised by health promoting factors – TrueScience Difference – 2015 no highlights
- The complexity of the Nrf2 pathway: beyond the antioxidant response. – PubMed – NCBI
- Oxidative stress in health and disease_ The therapeutic potential of Nrf… (1)
NRF2 – Activators, Overviews
- Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells – 2013 no highlights
- The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders – 2013
NRF2 – Activators, Curcumin
- “Curcumin, the King of Spices”: Epigenetic Regulatory Mechanisms in the Prevention of Cancer, Neurological, and Inflammatory Diseases. – PubMed – NCBI
- Curcumin as a regulator of epigenetic events. – PubMed – NCBI
- Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice – 2012
- Epigenetic impact of curcumin on stroke prevention
NRF2 – Activators, Vitamin D
- Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. – PubMed – NCBI
NRF2 – Cardiovascular Disease
- Phytochemical Activation of Nrf2 Protects Human Coronary Artery Endothelial Cells against an Oxidative Challenge – 2012
- Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. – PubMed – NCBI
- The Role of Nrf2 in the Attenuation of Cardiovascular Disease – 2013
NRF2 – Depression
- New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogress… – PubMed – NCBI
NRF2 – Diabetes
- Combating oxidative stress in diabetic complications with Nrf2 activators: how much is too much? – PubMed – NCBI
- Natural Nrf2 activators in diabetes. – PubMed – NCBI
NRF2 – Fasting/Calorie Restriction
- Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human – 2014
NRF2 – Inflammation
- A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. – PubMed – NCBI
- Nrf2-ARE stress response mechanism: a control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. – PubMed – NCBI
NRF2 – Kidney Disease
- Targeting the Transcription Factor Nrf2 to Ameliorate Oxidative Stress and Inflammation in Chronic Kidney Disease – 2013
NRF2 – Neurodegeneration, Nerve Damage
- NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage
- The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders – 2014
NRF2 – Obesity
- Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis – 2015
- The Role of Nrf2: Adipocyte Differentiation, Obesity, and Insulin Resistance – 2013
NRF2 – Ophthalmology
Central Serous Chorioretinopathy
NRF2 – Pain
- Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness – 2008
- The induction of human superoxide dismutase and catalase in vivo: a fundamentally new approach to antioxidant therapy. – PubMed – NCBI
- Roles of Reactive Oxygen and Nitrogen Species in Pain – 2011
Emphasis on Education
Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.
For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.
Should you wish more information regarding any of the subjects listed – or not listed – here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.
For more information, please contact Accurate Clinic.
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