By HVN’s Chief Scientist, Professor Richard Mithen
Photo: Cook’s Scurvy Grass (Lepidium oleraceum). Peter de Lange.
I was watching enthusiastic runners pass by while sitting sedately and drinking coffee, musing on the ‘antioxidant paradox’.
It is widely accepted that regular exercise can reduce the risk of many age-related chronic diseases such as type 2 diabetes, heart disease, cancer at several sites, and neurodegenerative syndromes. There is also a degree of consensus that as we age our organs become more subjected to oxidative stress, which at least partly underlies the enhanced risk of chronic disease.
As part of our normal metabolism our mitochondria – the engines within our cells – generate reactive oxygen species (ROS), which help to regulate many metabolic processes. As we age, our mitochondria become less efficient and generate too much ROS for our own good. The resultant increase in oxidative stress makes our tissues more susceptible to age-related chronic disease. Thus, we are advised to consume ‘antioxidants’ to maintain and promote our health.
And here lies the paradox: exercise increases oxidative stress.
As our muscles contract we burn up glucose and fatty acids derivatives in our mitochondria to generate ATP (packets of energy), and in so doing we generate excessive amounts of ROS, which would appear to be precisely the wrong thing to be doing.
Of course, the main resolution for this apparent paradox is that the benefit to health is not so much in the exercise-induced ROS generation, but in the recovery. The short, sharp shock of ROS stimulates our endogenous antioxidant defenses to be triggered, which restores our ‘redox’ balance. The response to excessive ROS, largely mediated through the ‘nrf2’ pathway , involves the increased expression of maybe two or three hundred genes that make proteins which mop up the excess ROS, re-tunes our metabolism and restores a healthy gene expression profile, and thereby reducing risk of age-related chronic disease.
Despite many intervention studies, there is little or no evidence that taking antioxidant supplements such as vitamins A (including β-carotene), C and E has beneficial effect upon health, and many studies suggest negative effects with increases in type 2 diabetes, cancer and all-cause mortality.
Moreover, taking antioxidant supplements negates the positive effect of exercise in enhancing insulin sensitivity. One explanation is that ‘flooding’ our bodies with these antioxidants may suppress the fluctuations in our redox status and the periodic triggering of our endogenous antioxidant defenses that have extensive and complex effects, far greater than the antioxidant supplements themselves.
What about the antioxidants in our foods? Our fruits and vegetables contain a myriad of natural chemicals that provide them their distinctive colour, taste and aromas. These are often referred to as ‘antioxidants’, and while they may have some antioxidant activities in the laboratory, when we consume them their beneficial effects are probably mediated through other biological processes with little or no effect on our endogenous redox status.
If exercise is so healthy, can we eat foods that mimic at least some of the positive effects of exercise? Can we lie on the couch and watch TV while giving ourselves a short, sharp shock of oxidative stress to trigger our endogenous defences and re-tune our metabolism?
Our supermarkets are packed with these foods – they are not labelled as ‘high in pro-oxidants’ but that is precisely what they do deliver. These are the vegetables and salads of the Brassicaceae (or Cruciferae) family – the broccoli, cabbage, kales and Pak Choi, and watercress, rocket, daikon and wasabi.
When we eat these plants, they generate mustard oils or isothiocyanates  that deplete our cells of glutathione (the major cellular redox sensor). We respond by switching on our antioxidant defences via nrf2 – just as we do with exercise – restoring glutathione levels and an efficient and healthy metabolism. And just like exercise, diets that are relatively rich in cruciferous vegetables and salads appear to protect us from a range of age-related chronic diseases, probably through the same fundamental molecular processes.
While our supermarkets have a good selection of these pro-oxidant Brassicaceae foods, none of them are native to Aotearoa New Zealand – all have been imported with successive waves of immigrants over the last few hundred years. However, Aotearoa does have a most interesting flora including its own native and endemic Brassicaceae species. Of particular note are the endemic and native Lepidium species of Aotearoa, known by Māori as nāu. These are mainly found in coastal habitats often associated with the burrows of sea birds and have become very scarce partly due to the diminishing populations of sea birds.
One of these endemics, Cook’s scurvy grass or Lepidium oleraceum, is reputed to have been gathered along with other shoreline vegetation by the crews of European vessels visiting New Zealand in the late 1700s and early 1800s to combat scurvy . Relatively few wild populations remain, but it can easily be found in the excellent rare plant section of the Auckland Botanic Garden.
For most of us, our knowledge of Lepidium is restricted to the species L.sativum or ‘garden cress’, grown on damp tissue paper by generations of school children and eaten in sandwiches. This species is native to the western Mediterranean and North Africa and is widely cultivated throughout Asia as a salad plant and for medicinal purposes.
In contrast, the other cultivated Lepidium species L meyenni or maca is endemic to the Andes where it has a long history as a medicinal plant. For many years, its cultivation was restricted to the high-altitude plateaus of Peru and Bolivia, but more recently it has been grown in China from seeds and tubers illegally smuggled out of Peru. The main reported effect of maca (apart from allegedly enhancing libido) is boosting energy and endurance – possibly by delivering that short, sharp shock of oxidative stress that triggers our antioxidative defences that re-tune our mitochondria enabling the delivery of a plentiful supply of energy.
 Oxidative stress is an imbalance between free radicals and antioxidants in your body. Free radicals or reactive oxygen species (ROS) are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. These reactions are called oxidation. The reverse reaction is called reduction. They can be beneficial or harmful. Antioxidants are molecules that can donate an electron to a free radical without making themselves unstable. This causes the free radical to stabilize and become less reactive.
 The main source of ROS is electron leakage through complex I and III of oxidative phosphorylation. ROS is an important modular of redox sensitive enzymes, including the TCA cycle enzymes succinate dehydrogenase, α-ketoglutarate dehydrogenase and isocitrate dehydrogenase, and thus as a negative feedback mechanism that regulates TCA cycle activity.
 It is possible that enhanced levels of ROS may irreversibly damage complex molecules such as lipids, proteins and DNA, but this is probably unlikely. A more probable cause of increase risk is the reversible inhibition of the catabolic functions of the TCA cycle and the resultant export of citrate and other intermediates to make new fats, amino acids and sugars and the changes is the epigenetic regulation of genes that result in a pro-inflammatory phenotype.
 Redox balance is a term used to describe an optimum chemical environment within our cells between an undesirable reductive state and an undesirable oxidative state. This is maintained through a dynamic equilibrium by endogenous and external (diet, exercise, injury) processes in which the redox states fluctuates along the reductive-oxidative continuum
 Nrf2 is a transcription factor that resides in the cytoplasm tethered to the Keap1 protein. When ROS increases, nrf2 is released and moves to the nucleus where it switches on an array of genes that restores a health redox status.
 Ristow (2104) Unraveling the Truth About Antioxidants: Mitohormesis explains ROS-induced health benefits. Nature Medicine 20, pages709–711
 Bjelakovic et al (2007) Mortality in Randomized Trials of Anti-oxidants Supplements for Primary and Secondary Prevention JAMA 297(8) 842 – 856
 Ristow et al (2009) Anti-oxidants prevent health-promoting effects of physical exercise in humans. PNAS 106(21): 8665–8670.
 Some of these isothiocyanates causes the hot and peppery taste of foods such as watercress, rockets and wasabi due to the interaction between the isothiocyanates and the TRPV 1 taste receptor, whereas other, and notably the isothiocyanate from broccoli known as sulforaphane, have little sensory effects.
 Scurvy grass is usually applied to Cochlearia officinalis – a coastal Brassicaceous plant of north western Europe which was presumably known to the crew of Cook’s antipodean voyages. It is debatable whether Cochlearia officinalis or Lepidium oleraceum has any more vitamin C than other shoreline plants.