We all know about antioxidants. They are the good things in our diet that protect us against the evils of damage caused by free radicals. However, recently in both scientific circles and consumer opinion there has been a rethink of the value of antioxidants, largely led by negative publicity from certain clinical trials (such as the one on beta-carotene).
Rethinking the value of antioxidants
This rethink was highlighted in a 2012 article in the industry newsletter newhope360: “Antioxidants as an ingredient category have suffered from the ‘magic pill’ syndrome. In the past 15 years these ingredients have soared on promises that remain mostly unfulfilled, and crashed on doubts that were overstated.”1
The author Hank Schultz goes on to write:1
“More than a decade ago information about the damage that free oxygen radicals can do in cells was becoming fixed in consumers’ consciousness. In a society focused on the attainment of eternal youth, free radicals, which had been linked to premature ageing, had become the new bogeymen. And new miracle molecules – antioxidants – were coming to the rescue, armed with the powerful weapon of high ORAC values. ORAC numbers (oxygen radical absorption capacity) began to be quoted on package labels. … This quick climb to the top began to be clouded by wavering doubts. First, there was the question of the ORAC test itself… Then there is the in vitro versus in vivo question. It doesn’t matter how good the sponge might be if you can’t use it to clean your kitchen.” (The in vitro versus in vivo question means that not all results produced in test tubes, such as ORAC values, translate into meaningful effects in living bodies.)
But in scientific circles, concerns over the value of antioxidants go much further than this. The key free radicals produced in the body (called reactive oxygen species [ROS] because they are based around oxygen) might sometimes exert beneficial effects. The discovery of ROS signalling (where free radicals trigger essential, healthy responses) has been verified as important in a variety of physiological functions, including glucose-stimulated insulin secretion and arming of defences against invading micro-organisms.2
To add fuel to the fire, there are new doubts over the oxidative stress theory of ageing mentioned above. This theory was first proposed by Harman in 1956: ROS inflict indiscriminate oxidative damage to cells that is not completely neutralized by antioxidants and/or repaired. Damage then builds up with time causing ageing. “Despite the intuitive logic and vast support for this theory, a causal link between oxidative stress and the rate of ageing has not been clearly established.”3
Ironically, at the same time there has been an intriguing new insight into how plant-based herbal chemicals (phytochemicals) exert their antioxidant activity in the body that completely blows away such negative concerns. It will also hopefully change the way you think about phytochemical antioxidants forever.
An unstated assumption of the antioxidant theory is that they are passive sponges of free radicals, often acting outside the cell because many of them, especially the herbal ones, cannot enter cells anyway because they are too large and/ or insoluble in the cell membrane. So to gain any significant protection against damaging free radicals you need to take large (possibly unrealistic) amounts of antioxidants, and once they are inside your body you cannot control any potentially negative radical-scavenging effects, because they are just passive sponges.
Antioxidant protection lies within every one of our cells
A new discovery completely changes this flawed assumption. An entirely novel cellular mechanism known as the Nrf2/ARE pathway describes a targeted approach to antioxidant protection within each and every living cell in our bodies. This primordial pathway, fundamental to all animal cells, is a dynamic response induced by oxidative or chemical stress on the cell. It is a switch-on, switch-off mechanism, and most of the priming agents studied so far that facilitate its action have turned out to be… yes, you guessed it… natural plant chemicals. Most importantly, it is a mechanism that only turns on when we need it.
So what exactly is the Nrf2/ARE pathway? A transcription factor is a cellular chemical that causes the DNA of the cell to manufacture specific proteins. Which proteins are manufactured depends on the transcription factor. Nrf2 is such a factor that is normally anchored in the cell cytoplasm (that is, outside the nucleus where the DNA resides) by a molecule known as Keap1. Chemical stress on the cell disrupts the tethering of Keap1 to Nrf2, releasing it. The free Nrf2 then moves (translocates) to the nucleus and there binds to the antioxidant response element (ARE), inducing the new synthesis of a range of antioxidant, detoxifying, protective and antiinflammatory enzymes.
Yes, that’s right. Not just antioxidant activity is induced by the Nrf2/ARE pathway, but a whole range (more than 200) of beneficial genes is activated. Nrf2 activation enhances DNA repair, haem metabolism, removal and breakdown of toxins and glutathione synthesis. It activates detoxification, stabilizes proteins, strengthens cellular integrity and reduces the inflammatory response.
Key antioxidant enzymes are produced, including catalase, superoxide dismutase (SOD), thioredoxin, peroxiredoxin, sulfiredoxin, ferritin, metallothionein and haem oxygenase 1 (HO1).4 Major phase II detoxifying enzymes are also triggered, including glutathione S-transferases (GSTs) and NAD(P)H: quinone oxidoreductase 1 (NQO1).3 “These functions likely represent only a fraction of the true function of Nrf2 activity, some of which are only beginning to be understood.”5
A few years ago an Australian colleague Dr Christine Houghton wrote the following:6 “What really put antioxidants on the map was the 1969 discovery of the core antioxidant enzyme, SOD (superoxide dismutase) by Duke University Medical School researchers, Drs Joe McCord and Irwin Fridovich. Their landmark paper describing SOD and its extraordinary clinical potential was the catalyst which spawned a whole industry around ‘antioxidants’ as supplements. … What McCord and Fridovich discovered was that the cell manufactures very powerful antioxidant enzymes, SOD, glutathione peroxidase and catalase and that these endogenous enzymes are catalytic in that they will quench a free radical and then recycle themselves and quench another and another and so on. What this means is that each antioxidant enzyme can quench literally billions of free radicals per minute. The reaction rate at which SOD quenches the superoxide radical has been measured at 2 x 109 free radicals per second… Compare this with any diet-derived antioxidant such as vitamin C where one molecule can quench just one single radical. Period! One single radical vs billions per minute!”
Harness the power of Nature to kick-start healing
And you can prime the production of these three key antioxidant enzymes inside your cell using the right herbal phytochemicals, where they are needed, and only when they are needed. The genius of Nature!
Surely harnessing such a powerful mechanism as the Nrf2/ARE pathway will have profound effects when it comes to maintaining health and managing disease. In fact, emerging research has already identified several important benefits of priming the Nrf2/ARE pathway to maintain health and prevent disease:
- healthy ageing and longevity
- protection against cancer development
- protection against radiation
- benefits in diseases involving oxidative damage and inflammation
- potential benefit in diseases resulting from accumulated toxins, even heavy metals
Let’s revisit the oxidative stress theory of ageing. Comparing different animals, we find that short-lived species have lower levels of Nrf2 together with nuclear binding activity, higher levels of Keap1, and lower production of the ARE enzymes. In other words, healthy longevity may not be so much about your exposure to free radicals, but more about how well-protected your cells are from free radicals by this pathway.3
Improving your Nrf2/ARE response could even protect you from contracting cancer, at least that’s what the experimental models suggest. In fact, most of the key phytochemicals known to prevent cancer in animal models of carcinogenesis are now thought to prime the Nrf2/ARE pathway as well. The combination of anti-inflammatory and antioxidant activity with detoxification represents a very powerful mechanism for resisting the cancer-causing potential of carcinogenic agents.7,8
Nervous tissue is richly endowed with fat, and as a result is highly prone to free radical damage. Beneficial effects of Nrf2/ARE priming/ activation have been suggested in neurodegenerative diseases including diabetic neuropathy,9 Alzheimer’s disease,10 Parkinson’s disease (PD),11 and age-related macular degeneration (AMD).12 HO-1 is a known neuroprotective heat shock protein/enzyme that, for example, protects against brain injury (from a stroke).13 In one study, cells from a biopsy of the olfactory mucosa had lower glutathione levels and detoxifying capacity in patients with PD compared with those from healthy control donors. These cells from PD patients were also in a state of oxidative stress due to higher levels of hydrogen peroxide. Significantly, activation of the Nrf2/ARE pathway restored those defective cells to normal.14
Positive effects of Nrf2/ARE priming have been suggested for lung diseases… with benefits extending to cigarette smokers and asthma, pulmonary fibrosis and emphysema patients. Cardiovascular diseases, autoimmune diseases and diabetes are also in the list of diseases that might benefit.15 The lungs are the tissues in the body most exposed to oxygen because of their very high surface area, and often suffer greatly from damage by ROS.
In Part 2 of this article I will describe the key herbs/ phytochemicals known to prime the Nrf2/ARE pathway. These are the true antioxidants of the future that you can benefit from right now.To your better health,
Nutrition & Healing
Volume 6, Issue 11 – November 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.