What are the key herbs/ phytochemicals with Nrf2/ARE priming activity? The research has focused on just a few key ones: sulforaphane from broccoli (especially the sprouts), curcumin from turmeric, resveratrol, carnosol from rosemary, ginkgo extract, the polyphenols from green tea, and the sulphur compounds in garlic.
Cruciferous cancer fighters
The consumption of cruciferous vegetables has long been associated with a reduced risk of cancer at various sites in the body. The key chemo-preventative phytochemical sulforaphane is found in certain cruciferous vegetables and is especially high in broccoli sprouts.1 It is believed to react with the cysteine amino acid residues in Keap1. As well as Nrf2-mediated induction of cellular defences, many other mechanisms have been proposed for chemo-prevention by sulforaphane and these appear to act synergistically.2 Broccoli sprouts have reduced measures of oxidative stress in type 2 diabetes patients in a clinical trial.3
The spice connection
Rosemary contains the antioxidant molecules carnosol and carnosic acid. Both of these are now understood to be potent primers of the Nrf2/ARE pathway. For example, they have demonstrated neuro-protective activity by this pathway, which reflects on rosemary’s traditional use for memory.4,5 Recently, a single 750mg dose of rosemary improved the speed of memory and alertness of healthy older adults.6
Multiple animal lab studies have demonstrated the chemo-preventative activities of curcumin and turmeric.7 The Nrf2/ARE pathway is thought to be an important basis for these effects. For example, the epigenetic silencing of Nrf2 during the progression of prostate tumours in a mouse model was reversed by curcumin.8 Brain and liver injury were reduced by curcumin through Nrf2-mediated induction of HO-1.9,10 Dietary curcumin led to increased Nrf2 protein levels and enhanced ARE binding in the liver and lungs of mice.11
A significant proportion of the health-promoting activity of green tea and its key component EGCG is now thought to be via the Nrf2/ARE pathway.12 These activities include chemo-preventative, neuroprotective, detoxifying, and antioxidant outcomes. These beneficial effects for green tea are not seen in Nrf2-deficient animal models.
Resveratrol’s powerful protection
Resveratrol is a highly active primer of the Nrf2/ARE pathway. Favourable Nrf2-mediated protection has been demonstrated in many body systems including the endocrine, cardiovascular, and nervous systems. For example, the endothelial (circulatory) protective effects of resveratrol against a high-fat diet were largely diminished in Nrf2 knockout mice.13
In a recent double-blind, randomised, crossover study, 10 normal, healthy men and women were given a high-fat, high-carbohydrate (HFHC) meal (930 kcal) either with a placebo or a product containing 100mg of resveratrol from Polygonum cuspidatum plus 75mg of total polyphenols from a grape extract.14 The DNA binding activity of Nrf2 in white cells was significantly increased by 150 ± 39 per cent over baseline at three hours after the meal and supplement intake, whereas meal consumption in the placebo group resulted in a significant reduction in Nrf2 binding activity at five hours. These were associated with a significant reduction of Keap1 by 48 per cent in the supplement group and a significant increase by 66 per cent in the placebo group.
Ginkgo deflects damage
Ginkgo is now well known as a powerful clinical antioxidant. Its antioxidant properties could play an important role in protection against radiation damage and appear to be mediated by Nrf2. In an uncontrolled trial conducted in 1995, ginkgo extract protected against radiation-induced DNA damage in Chernobyl workers.15 More recently, the same dose of extract (120mg/day) protected against DNA damage caused by radioactive iodine treatment in patients with thyroid disease.16
There have been many trials of ginkgo and stroke recovery in China and the Cochrane Collaboration published a systematic review and meta-analysis.17 While the review expressed concerns about the quality of most trials, it did find that ginkgo was associated with a significant increase in the number of improved patients, based on neurological symptoms. Induction of HO-1 via Nrf2/ARE activation by ginkgo has been suggested as a significant mechanism for neuro-protection and recovery following cerebral ischaemia.18,19/span>
So this new understanding has the potential to provide us with herbs that can benefit health by:
- providing clinically relevant, safe, targeted antioxidant cover
- supporting anti-ageing/ healthy longevity protocols
- supporting the detoxification of ANY toxin: drugs, alcohol, smoking, heavy metals, etc.
- facilitating protection against ANY physical or biological stressor: especially radiation and heat stress
- reducing cancer incidence
- reducing cancer recurrence (but they are not to be used during chemotherapy or radiotherapy, see later)
- reducing neuro-degeneration as in macular degeneration, Alzheimer’s and Parkinson’s diseases, stroke recovery and diabetic neuropathy
- acting as key moderators in any chronic inflammatory disease, such as osteoarthritis and autoimmune diseases
- acting as key preventative and palliative agents in cardiovascular disease, especially for arterial and endothelial damage/ dysfunction
- helping to counter the negative metabolic effects of a high-fat and/or high-fried/ food diet
- providing protective cover during weight loss
- improving metabolism in diabetes and metabolic syndrome
- supporting the lungs in any chronic lung disease
Why wouldn’t you take these herbs every day? In fact, many of us do, either in our diets or as supplements. I certainly do.
The 48-hour rule
There is just one cautionary note, Nrf2 and its downstream genes are over-expressed in many experimental cancer cell lines and human cancers, giving cancer cells an advantage for survival and growth. Also Nrf2 is upregulated in cancer cells resistant to chemotherapy and is thought to be responsible for acquired chemo-resistance. Therefore it may prove advantageous to inhibit the Nrf2/ARE pathway during chemotherapy.20 There are still many questions to be answered. However, caution dictates that any known Nrf2/ARE upregulating herbs should not be taken at least 48 hours either side of each chemotherapy or radiotherapy treatment, so the cancer-killing effects of these treatments is not interfered with.
As a final reminder, the key herbs/phytochemicals identified by current research that are most active at priming the Nrf2/ARE pathway are: broccoli sprouts/sulforaphane and garlic, turmeric/curcumin, rosemary and green tea/EGCG, and resveratrol and ginkgo.
To your better health,
Nutrition & Healing
Volume 6, Issue 12 – December 2012
Full references and citations for this article are available in the downloadable PDF version of the monthly Nutrition and Healing issue in which this article appears.