Chapter 1: Dietary Supplements with Antioxidant Activity – Understanding Mechanisms and Potential Health Benefits: An Overview Free

Antioxidant supplementation, either in the form of tablets/capsules and potions or in foods, is based on the notion that reactive oxygen species (ROS) and other free radicals contribute to many human diseases by causing oxidative stress and that decreasing oxidative damage may help to prevent their occurrence. Therefore, the assumption that antioxidants are good for health and that consuming antioxidants will improve health is commonly accepted by the general public.¹ 

Many diet-derived substances can act as antioxidants. The most familiar ones are some vitamins (such as vitamins C, E, K, β-carotene, and folic acid) and minerals (such as selenium and zinc), along with cofactors (such as coenzyme Q10). There are also many different classes of bioactive phytochemicals (such as alkaloids, betalains, carotenoids, flavonoids, phenolic acids, coumarins, phytoestrogens, non-protein nitrogen compounds, organosulfur compounds, stilbenes, and tannins, among others) which have been reported to possess strong antioxidant activities.^2–7  Moreover, long-chain omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from marine sources⁸  and essential oils from medicinal herbs⁹  either exert an antioxidant effect or are involved in the oxidation process that benefits from the use of antioxidants. Figure 1.1 shows the representative diet-derived antioxidant substances and their health outcomes.

In addition to diet-derived antioxidants, there are also endogenously-synthesized primary (such as superoxide dismutase, catalase, and glutathione peroxidase) and secondary (such as glutathione reductase enzymes) antioxidant enzymes. The overall antioxidant defence in the human body depends on endogenously-synthesized antioxidant enzymes, which serve as the primary defence, whereas diet-derived antioxidants (food and supplements) are categorized as secondary defence.^1,10,11  This contribution provides some important highlights about antioxidants from dietary supplements and natural sources by discussing their potential mechanisms and health benefits.

Excessive free radicals generated in vivo increase cellular oxidative stress. Chronic oxidative stress is a common pathophysiological condition that causes chronic oxidative damage and finally inflammation. Chronic inflammation is the major determinant of various non-communicable diseases (NCDs) later in human life, contributing to ageing, cardiovascular disease (CVD), diabetes, cancers, obesity, and neurodegenerative diseases (NDD) such as dementia and Alzheimer's disease.^10,11  Hence, taking dietary antioxidants in the form of food or supplements decreases oxidative damage in vivo and may help to prevent the severity of NCDs.^1,11 

However, the dosage of administered dietary antioxidants may not always be accurate as this often exceeds the recommended dietary allowances (RDA) when used as a supplement. Thus, lower doses and/or mixtures of antioxidants are superior to high doses of single agents.^10,12  For example, consumption of foods rich in vitamin C was shown to decrease oxidative damage physiologically, whereas the intake of vitamin C alone at high dosage did not. In this relation, a study demonstrated an increased plasma vitamin C level by 60% after daily supplementation with 500 mg of vitamin C for 6 weeks. However, the pro-oxidant activity of vitamin C was also noticed as significantly higher levels of 8-oxoadenine in DNA were present in blood lymphocytes.¹³  In fact, the use of vitamin C at a dosage of 1.000 mg for optimal health far exceeded the RDA of 75–90 mg per day.¹⁴  Vitamin E, in the form of α-tocopherol, becomes a pro-oxidant at high concentrations (>700 ppm), both in food and in the body.¹⁵ 

Polyphenols are the most active naturally occurring antioxidants.¹⁶  Most dietary polyphenols have both antioxidant and prooxidant properties depending on the dose and environment.¹⁷  (−)-Epigallocatechin-3-gallate (EGCG) has been used as a dietary supplement for the control of obesity. However, it triggers adverse reactions, such as hepatotoxicity, among some consumers.¹⁸  The prooxidant capacity of a polyphenol largely relies on its autoxidation, its ability to produce ROS, including hydrogen peroxide. Oxidation of phenolic compounds, such as gallic acid, (−)-epigallocatechin (EGC), catechin, quercetin, hydroxytyrosol, rosmarinic acid, and delphinidin, as well as thiol compounds, generates hydrogen peroxide which contributes to cellular oxidative stress.^19,20  Transition metal ions, such as copper, promote EGCG oxidation and produce highly harmful hydroxyl radicals.²¹  Resveratrol, a stilbene with high antioxidant capacity, has a pro-oxidant effect in the presence of copper.²²  It is well known that every compound has negative effects if overdosed. This is the same for antioxidants. The consumption of high doses of antioxidants could be the main reason for the increased toxicity reported, leading to prooxidant effects or “antioxidative stress”.²³ 

There are numerous meta-analyses, systematic reviews, observational studies, and human intervention trials that demonstrate no beneficial effect of multi-vitamin or multi-mineral antioxidant supplements on all-cause mortality, cancer, CVD, and cognitive functions, among others.^24–29  Moreover, it was found that β-carotene, vitamin E, and possibly high doses of vitamin A supplements may be associated with higher all-cause mortality.²⁹ 

In reality, certain antioxidant supplements demonstrate positive effects and good efficacy. Many supplements, including vitamins, minerals, and other functional ingredients such as probiotics, are important components of modern health care.³⁰  Dietary supplements are important in preventing vitamin and mineral deficiencies, and some studies have demonstrated that a specific combination of vitamins and minerals can delay progression of early age-related macular degeneration.²⁴  However, supplements that are useful in treating certain conditions are frequently overused among the general population to improve or maintain health.^27,30  Therefore, full attention needs to be paid to the dosages of all supplements consumed and moderate rather than mega-dose consumption of antioxidants (in the form of tablets or capsules) is recommended.¹ 

Natural antioxidants are widely distributed in foods, beverages, and medicinal plants. The notion of “Let food be thy medicine and medicine be thy food” advocated by Hippocrates some 2500 years ago is still relevant today. It is a known fact that all foods are functional since they provide nutrients, flavour (taste and aroma), and bioactive phytochemicals.¹⁶ 

Consumption of fruits, vegetables, beverages, cereals, grains/seeds, nuts, mushrooms, spices, and medicinal herbs, among others, helps maintain good health and delay disease occurrence. In addition, industrial processing of agricultural by-products also provides potentially important natural sources of antioxidants.^1,7,31,32  The intake of 3–5 daily servings of fruits and vegetables would protect against NCDs such as coronary heart disease (CHD), cancer, NDD, diabetes, and obesity, among others.³³  This is because fruits and vegetables are chemically complex, where their health benefits could arise from the overall effects of several compounds or mixtures of components present, including vitamins, minerals, fibres, and bioactive phytochemicals. This mechanism is known as a synergistic action where the observed effects exceed the sum of individual effects in complex biological systems.^1,16 

These natural antioxidants, especially polyphenols and carotenoids, exhibit a wide range of biological effects, including anti-inflammatory, anti-aging, anti-atherosclerosis, and anti-cancer.^3,6  The effective extraction and proper assessment of antioxidants from food and medicinal plants are crucial to explore the potential antioxidant sources and promote the application in functional foods, pharmaceuticals, and food additives.³² 

The potential mechanism of protective action of antioxidant compounds is thought to be due to their direct scavenging of free radicals that include ROS, reactive nitrogen species (RNS), and lipid peroxides.¹⁶  Besides, antioxidant compounds inhibit the initiation step or interrupt the propagation step of lipid oxidation, thus reducing the formation of volatile decomposition products (e.g., aldehydes and ketones) that cause rancidity. This action prolongs the oxidative stability of food.¹⁶  Antioxidant compounds alleviate oxidative damage by activating endogenous antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase).¹  Mitochondria are not only the energy providers to maintain cell life activities, but also the regulators of cellular oxidative stress. Thus, changes in mitochondrial function are closely related to oxidative damage to cells.³⁴  Antioxidant compounds have been shown to alleviate oxidative damage by regulating mitochondrial function by adjusting the protein and gene expression levels of Bax, Bcl-2, caspase-3, and cleaved caspase-3.³⁴  Moreover, antioxidant compounds regulate the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways to upregulate genes [MAPK kinases, extracellular-signal related kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK)1/2] related to oxidative stress, thus reducing the production of pro-inflammatory cytokines, which in turn decrease endogenous inflammation.^8,35  This, in turn, enhances the phosphorylation level of PI3K/Akt and its activity, which activates NF-E2-related factor 2 (Nrf2). Then, Nrf2 further promotes the antioxidant enzymes [quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1)] to remove ROS.³⁶  The available evidence indicates that the induction of HO-1 is in conjunction with neuroprotection against various stimuli, including glutamate and erastin.³⁷  In this relation, antioxidant compounds also enhance the phosphorylation level of MAPK to remove ROS. Hence, antioxidants recover the mitochondrial function to make cells metabolize and function normally.³⁴  Figure 1.2 summarizes the complex mechanisms of action of antioxidant compounds from food/supplements from previous studies.

There are several misconceptions about antioxidants and free radicals in human physiology. Humans have a well-balanced pool of free radicals and antioxidants that allow some free radicals to perform useful functions while alleviating oxidative damage in vivo. ROS detoxify pathogens as part of the human innate immune system.³⁸  In addition, ROS also detoxify some infectious microorganisms. Phagocytes use ROS to kill pathogens in innate immunity.^11,38  In fact, free radicals are needed by stem cells for proper functioning. However, excessive free radicals may affect their function.³⁹ 

The overall antioxidant defence in the human body depends mainly on the endogenous antioxidant enzymes, such as reduced glutathione, catalase, peroxiredoxins, and superoxide dismutase. Meanwhile, diet-derived antioxidants (e.g., vitamins A, C, and E, and phenolic compounds) are classified as secondary defence. The antioxidant defence system functions to minimize the levels of most harmful ROS on one hand, while allowing adequate levels of ROS for their useful functions, such as cell signaling and redox regulation. Therefore, the antioxidant defence system will be more effective if it is stimulated with some weak or mild prooxidants or free radicals. This, in turn, stimulates the level of endogenous antioxidants in the body, such as glutathione and superoxide dismutase to combat infections.^11,12  On the contrary, over-consumption of antioxidants could down-regulate important endogenous antioxidant enzymes, depressing the immune system partially.^11,12 

Antioxidant compounds from food/supplements exert their effects by directly scavenging free radicals, activating endogenous antioxidant enzymes, regulating mitochondrial function, and reducing cellular inflammation. Consumption of natural foods rich in antioxidants such as fruits, vegetables, nuts, grains, and medicinal plants may provide a better option for health promotion and disease risk reduction compared to taking high dosages of dietary antioxidant supplements. Since natural foods are chemically complex and their health benefits could arise from the overall effects of several bioactive compounds of mixtures of components present, including vitamins, minerals, fibres, and bioactive phytochemicals. High-dose antioxidant supplements may not always benefit human health, while moderate presence of prooxidants in the body may sometimes be helpful for stimulating the overall immune response to external hazardous compounds.