ALL ABOUT ANTIOXIDANTS

antioxidant 01

A lot of hype surrounds a group of compounds called “antioxidants”. According to a recent review, a Google search combining the words “antioxidant” and “health” gives over 82 million hits, exemplifying the popularity of this topic.34

Antioxidants came to public attention in the late 80s, when scientists began to understand that the so-called free radicals are involved in the development of atherosclerosis and may contribute to several types of cancer, eye diseases, and a number of other chronic medical conditions.

From that time, clinical trials have begun testing the impact of antioxidant-rich foods, as well as single antioxidant substances (such as beta-carotene, vitamin C and E, glutathione, alpha-lipoic acid, coQ10 etc.) on heart disease, cancer, and other chronic diseases.

A number among these studies suggested that people who ate few antioxidant-rich foods had a greater risk of developing these medical conditions. As a result, the benefits of antioxidants was glorified by the media and by the food industry, that began hyping anti-oxidant rich foods and the health benefits of antioxidant supplements.

This is why we hear a lot of talk about how great they are for us, and we should find ways to eat them anyway and any where we can. This may seem like common knowledge, but what is not so commonly known is exactly why antioxidants are good for us, and even what antioxidants actually are?

 

FIRST THINGS FIRST: WHAT ARE FREE RADICALS?

During our everyday life, various metabolic processes takes place in our body. Also, our external environment affects metabolic processes. As a result, various molecules are generated while others are broken down. A part of the molecules formed during these processes are friendly while others are not, and can be damaging to our cells. The so-called free radicals are a group of the latter type of molecule. 

In chemistry, a free radical is an atom, molecule, or ion that has an unpaired valence electron. These unpaired electrons make radicals unstable and highly chemically reactive.

This may sound a bit complicated for some, so to help you understand free radical structure, role, and physiological effects, here is a short abstract about the chemistry of radicals and antioxidants. You can skip it, and continue reading the later part of this article, but these things can be crucial. If you would really like to understand them, I promise you that it won’t be too complicated. A big part of these things may sound familiar to you from your schooldays.

 

SHORT CHEMICAL BACKGROUND

All matter in our universe, solid, liquid, gas, or plasma, is composed of atoms. These are the smallest constituent unit of ordinary matter that has the properties of a chemical element. If two or more atoms are linked together, they become what we know as molecules.

Every atom is composed of a core or nucleus made of one or more protons and neutrons, and of electrons that revolve around the core.

Electrons that occur together in a nuclear orbit are called an electron pair. As the formation of electron pairs is often energetically favorable, atoms and molecules are most stable if each orbital contains paired electrons. On the other hand, an entity that carries an unpaired electron is usually reactive and unstable. These are the so-called free radicals. Free radicals are an atom or molecule that has an unpaired electron and is extremely reactive. It is capable of engaging in rapid change that attacks, damages and destabilize other molecules.

There are many types of radicals, but those of most concern in biological systems are derived from oxygen, and known collectively as reactive oxygen species (ROS).

 

HOW DO RADICALS AFFECT OUR BODY?

As we mentioned before, free radical formation occurs continuously in our body. They can be derived either from normal metabolic processes, such as when we convert food to energy, or when we exercise. They can also occur from external sources such as exposure to UV irradiation, X-rays, ozone, pollutants (cigarette smoke, air pollution), toxins and industrial chemicals.

The unpaired electron makes them unstable and highly reactive, and thus they attack important structures in our body and react with biologically relevant molecules such as DNA, proteins, carbohydrates, and lipids, leading to cell damage.

But before we’re going further, you have to understand that radicals are not evil per se!

In fact, free radicals are absolutely essential to life, and are involved in a number of vital biochemical and physiological processes. For example, they are an important part of the body’s defense against infectious agents, and in the function of a number of cellular signaling systems.

But at high concentrations, they can cause damage to cell structures. So, they can be both harmful and beneficial in our body depending on the environment, and their level. This is why our body has a number of mechanisms to minimize radical-induced damage and to repair damage that occurs. This is where antioxidants come in!

 

ANTIOXIDANTS

The harmful effects of free radicals are balanced by the action of antioxidants. In many cases their role is simplified, and two principle mechanisms of action have been proposed for antioxidants.

The first is a chain-breaking mechanism by which the antioxidant donates an electron to a rampaging free radical and neutralizes it, thus reducing its capacity to damage. The second mechanism involves removal of radicals by quenching chain-initiating catalyst.

This may help you understand their main role, but if we would like to be exact we should note that antioxidants act in defense systems at different levels, such as preventive (suppress the formation of free radicals) and radical scavenging (suppress chain initiation and/or break the chain propagation reactions). The third line of defense is the repair and de novo antioxidants, and there is another important function called adaptation. 1, 62, 63

But, for now, we only need to understand that antioxidants are specific substances that may prevent or delay free radical induced tissue damage, mainly by preventing the formation of radicals, scavenging them, or by promoting their breakdown. 32, 33

 

DISTURBED BALANCE – OXIDATIVE STRESS

Now you can understand that both free radicals, as well as antioxidants are vital for life.

We cannot live without either, so as with most of the things in our life, we have to find and build a balance. We need the right level of free radicals for our daily functioning, but we also need the right level of antioxidants to keep them in check.

When this balance gets disrupted, things can start to go wrong. Oxidative stress is a condition when the critical balance between radical generation and antioxidant defenses is unfavorable.1

Short-term oxidative stress may occur from time to time in our body in tissues injured by trauma, infection, toxins, excessive heat, hyper-, or hypotoxia, and even by excessive exercise.

But in addition, our modern highly stressed lifestyle, with its processed foods, reliance on medications, high exposure to chemicals, toxins and other environmental pollutants seems to lay the foundation for the proliferation of free radicals, and causes prolonged oxidative stress that leads to an increased risk of negative health outcomes.

Chronic oxidative stress is thought to make a significant contribution to aging and age-dependent diseases, inflammatory, cardiovascular and ischemic diseases (such as heart diseases and stroke), certain types of cancer, gastrointestinal diseases, neurological and neurodegenerative disorders, and many others afflictions.1-5

 

ENDOGENOUS AND EXOGENOUS/DIETARY ANTIOXIDANTS

As we saw, free radicals are a product of tissue metabolism, and the potential damage which they can cause have to be minimized by the antioxidant system and repair mechanisms within the cell. Our body deals with the pathological effects of radicals by utilizing the endogenous antioxidantsystem, and by the ingestion of exogenous antioxidants as a part of a diet or as dietary supplements.

The most important enzymatic antioxidants produced by our body are glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD).

Non-enzymatic antioxidants include Vitamin E, VitaminC, so-called thiol antioxidants (such as glutathione, thioredoxin and lipoic acid), melatonin, carotenoids, natural flavonoids, and other compounds. 1, 5, 6, 7, 8, 10

Besides their direct effects, some antioxidants can interact with other antioxidants regenerating their original properties. This synergic system is often referred to as the “antioxidant network”. Some dietary compounds do not directly neutralize free radicals, but enhance endogenous activity of other antioxidants, or support their function. These may also be classified as antioxidants or as co-factors. 1, 5, 6, 7, 8, 10

For example, various antioxidant enzymes have a requirement for specific compounds for their activity. Zinc, selenium, manganese, iron, riboflavin (Vitamin B2), thiamine (Vitamin B1), coenzyme Q10 (Co Q10), and carnitine are all considered as important co-factors involved in antioxidant defense mechanisms.

 

NUTRIENTS WITH RADICAL-QUENCHING PROPERTIES

Our endogenousantioxidants play a key role in maintaining normal cellular functions and thus health and well-being. Under conditions of high and prolonged oxidative stress, however, endogenous antioxidants may not be sufficient and dietary antioxidants may become even more important to maintain optimal cellular functions.

A combination of endogenous and exogenous antioxidants in metabolically active tissue cells in a healthy subject with an adequate dietary intake, damage to tissue will be minimal and most of the damage occurring will be repaired.17

Exogenous antioxidants are part of our daily diet, mainly in fruits, vegetables, beverages, spices, and herbs. It is now well established that persons consuming generous amounts of these foods have a lower risk of chronic disease than do those whose intake is small. In fact, low consumption of vegetables and fruit contributed to more than 3.8 million deaths in 2016!18, 19, 20

A review of 95 individual studies, found that there was a 16% reduction in the risk of heart disease, a 28% reduction in the risk of stroke, a 22% reduction in the risk of cardiovascular disease, a 13% reduction in the risk of cancer, and a 27% reduction in the risk of all-cause mortality for an intake of 500 g of fruits and vegetables per day, compared to 0–40 grams per day.20

According to the WHO antioxidant nutrient requirements of the general population can be met by a generous consumption of fruit and vegetables. The slogan “5 portions a day” has been promoted to publicize this idea.17

The WHO has also highlighted that certain groups may have an increased risk of free radical-initiated damage:

  • People who smoke are exposed to free radicals inhaled in tobacco smoke. Cigarette smoke is a complex mixture of more than 7,000 compounds, and more than 90 of them are placed on the cigarette-related carcinogens and toxins list of the the U.S. Food and Drug Administration’s list of hazardous and potentially hazardous chemicals.17, 31
  • Alcohol consumption. People abusing alcohol need to develop increased metabolic capacity to handle the extra alcohol. Alcoholic drinks are also classified as a human carcinogen, and the National Cancer Institute emphasizes that because alcohol creates free radicals in the body, it can lead to an increased cancer risk.
  • Toxins, bacterial, viral, and fungal infections, certain drugs, pesticides, industrial solvents also increase free radical formation, as well as excessive UV irradiation, including sunbathing.1, 17 Higher risks may be faced by people working in environments with elevated levels of volatile solvents (e.g., petrol and cleaning fluids, in distilleries, chemical plants, etc.), and also by car drivers and other people working in dense traffic may be exposed to elevated levels of exhaust fumes. 17
  • People with untreated high blood sugar levels, and diabetes might also be exposed to increased free radical damage. Aside from hyperglycemia, there are several other factors that play an important role in pathogenesis of diabetes, such as oxidative stress. 28
  • Excessive physical activity. It may sound a little paradoxical, but in general, exercise is known to reduce oxidation levels in serum. This is possibly associated with an increase in antioxidant enzymes. Initially, however, when exercise intensity is excessive, an adaptation phase takes place. This phase is associated with an increase in oxygen intake, as well as the activation of specific metabolic paths during physical exercise, which may result in the increased formation of free radicals. People involved in acute or chronic physical exercise programs should avoid overtraining. If they must be engaged in high intensity training, they may benefit from antioxidant supplementation. 29, 30
  • High consumption of red meat, processed meats, processed oils also increase free radical generation and levels. Fats and oils may oxidize during storage because of exposure to light, air or heat, leading to free radical formation. Cooked and processed meats can also become oxidized at high temperatures because of fats in the meat, and because of iron in red meat. Meanwhile, preservatives added to sausages, bacon, ham, hotdogs, salami, corned beef and deli meats can also prompt free radical production.
  • People with sleep disturbance and sleep problems. Sleep functions essentially as an antioxidant for the brain. According to the theory of sleep, cerebral radicals accumulate during wakefulness and are removed during sleep. Removal of excess free radicals during sleep is accomplished by decreased rate of formation of free radicals, and increased efficiency of endogenous antioxidant mechanisms. In fact, studies revealed that the free radicals formed as a result of hypoxia and oxygenation are responsible for the cardiovascular and cognitive problems in obstructive sleep apnea syndrome patients.27
  • Premature infants are also at increased risk of oxidative damage because they are born with immature antioxidant status. 17

So, we can conclude that in our modern world we are exposed to very high rates of oxidative damage from a very young age. This means we have a high demand for a powerful antioxidant defense. In general, It’s always ideal and more beneficial to get antioxidants, as well as other nutrients directly from real food sources, but certain types may also be helpful when consumed in supplement form. Let’s look a little closer at the role of some of the most important nutrients in this field.

Vitamins C and E are the principal antioxidant nutrients. The most important difference between them is their soluability. Vitamin C is water soluble and is therefore especially found in the aqueous fractions of the cell and in body fluids. Vitamin E is fat-soluble, so its main action is in cell membranes and lipoproteins.1

Vitamin E is a fat-soluble vitamin that is exists in eight different forms. The form known as alpha-tocopherol is the most active form in the human body. In fact, in plasma samples of vitamin E, more than 90 percent is present as alpha-tocopherol.

The main function of vitamin E is that of an antioxidant. Its main site of action is cell membranes, because fats, which are an integral part of all cell membranes, are vulnerable to damage by free radicals, through a process called lipid peroxidation.

Aside from the protection of cell membranes, vitamin E also protects the fats in low-density lipoproteins (LDL) from oxidation which transport cholesterol from the liver to the tissues of the body. Oxidized LDLs have been implicated in the development of cardiovascular disease.77

When a molecule of alpha-tocopherol neutralizes a free radical, it is oxidized and converted to a radical. This alpha-tocopherol radical can be reduced to the original alpha-tocopherol form by ascorbic acid (Vitamin C).1, 77

 

Early observational studies, including the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS), suggested a 20-40 % reductions in coronary heart disease risk among individuals who took vitamin E supplements (400 IU on average) for at least two years.78, 79, 80 More recent evidence is somewhat ambiguous, suggesting that vitamin E may have potential benefits only in certain subgroups who have greater oxidative stress from genetic predisposition, health condition or lifestyle factors.77

Vitamin E’s role in cancer prevention may also be controversial, but according to the reports from the Cancer Institute of New Jersey, vitamin E (in the form of gamma- and delta-tocopherols) effectively work against colon, lung, breast and prostate cancers. 81, 82, 83

Besides the above-mentioned diseases, vitamin E has been found to play a beneficial role in other degenerative diseases like arthritis, neurological disorders such as Alzheimer’s disease, tardive dyskinesia, eye conditions including cataracts, photodermatitis, and menstrual pain / dysmenorrhoea, pre-eclampsia. 1, 12, 13, 77.83

In addition, it may also have a pronounced effect on infectious diseases. Its supplementation significantly enhances immune functions and resistance to viral diseases, especially in the elderly.81, 84, 85, 86

 

Major dietary sources of vitamin E include vegetable oils (such us olive, sunflower, and safflower oils), nuts, seeds, fish-liver oil, green leafy vegetables, whole grains (concentrated in germs) and sea buckthorn.

Vitamin C or ascorbic acid is synthesized from glucose in the liver of most mammalian species, but not by humans, non-human primates and guinea pigs. In humans, it has to be ingested for survival.

The importance of vitamin C was first discovered in 1747. 16th century sailors died from scurvy, a disease caused by acute lack of vitamin C. The term ascorbate is derived from scurvy to describe its ability to prevent scurvy.66, 67, 68

Vitamin C is a powerful water-soluble antioxidant and plays a major role as a free radical scavenger. 64 It is a potent reducing agent, meaning that it readily donates electrons to recipient molecules. Related to this potential, its two major functions are as an antioxidant and as an enzyme cofactor.

It regenerates Vitamin E, and also raises levels of, and aids the function of other antioxidants. It plays a very important role in the antioxidant network.1, 64, 66

Prospective cohort studies indicate that higher intakes of vitamin C from either diet or supplements are associated with a reduced risk of cardiovascular disease (CVD), including coronary heart disease and stroke. 65, 66 Studies indicate that higher blood levels of vitamin C are associated with lower risk of death from all-causes, cancer, and CVD.66, 69, 70

Its protective role has been investigated and proved in various other diseases, such as certain types of cancer (such as breast cancer71, 72, stomach cancer73,74, 75, Non-Hodgkin lymphoma60,76), aging and age-related disorders, arthritis, eye conditions just to name a few.11, 12 In the eye, vitamin C concentrations may be 50 times higher than in the plasma and may protect against the oxidative damage of light,. Vitamin C is also present in high quantity in the gonads, where it may play a critical role in sperm maturation. 17

 

Major dietary sources of vitamin C include citrus fruits and their juices (such as oranges, sweet lime, grapefruit), kiwi, green peppers, broccoli, green leafy vegetables, black currants, strawberries, blueberries, sea buckthorn, cabbage and tomatoes.

Carotenoids are a class of more than seven hundred naturally occurring pigments present in plants and microorganisms. Among these a relatively few are found in human tissues. The six main ones are beta-, and alfa-carotene, lutein, zeaxanthin, lycopene, and beta-cryptoxanthin.17

In plants, carotenoids have the important antioxidant function of deactivating oxidants formed during photosynthesis. Carotenoids contain conjugated double bonds and their antioxidant activity arises due to the ability of these to delocalize unpaired electrons.

Various prospective studies found that higher plasma carotenoid level has been associated with significant reductions in risk of cardiovascular disease46-50, It has also been found that people with higher intakes of carotenoid-rich fruit and vegetables are at lower risk of cardiovascular disease.51-54

In cancer prevention, their roles are controversial, but a meta-analysis of 8 prospective cohort studies, including NHS (Nurses’ Health Study) and HPFS (Health Professionals Follow-Up Study), found that higher carotenoid intake was significantly associated with a reduced risk of lung cancer, especially beta-cryptoxanthin and lycopene.57

In addition, several meta-analyses proved a beneficial effect of specific carotenoid molecules in specific cancers. For example, studies found that men with higher intake of dietary lycopene had lower risk of prostate cancer.40, 58

In an review of 15 individual studies, a reductions in breast cancer risk were found to be associated with blood concentrations of total carotenoids, alpha-carotene, and lutein. 59 It has also been found that higher intakes of beta-cryptoxanthin and lycopene, might be associated with a reduced risk of cancers of the mouth, pharynx, and larynx,61 while another review found a 31% lower risk of colorectal cancer with the highest versus lowest quartile of beta-carotene intake.60

Additional note about their safety for heavy smokersIt has to be noted that under certain circumstances carotenes can also act as a pro-oxidant causing an increase in lipid peroxidation, depending on the concentrations of carotenoids and the partial pressure of oxygen. For example, beta-carotene exhibit antioxidant properties at low oxygen partial pressure but become pro-oxidants at high pressures of oxygen. Similarly, when high carotenoid concentrations are present, pro-oxidant behavior is displayed. This is why there was some concern about a possible link between the ingestion of high dose of beta-carotene and cancer enhancement in heavy smokers.

In recognition of such a possible correlation, a number of study investigated. Recent epidemiological studies reported no increased lung cancer incidence in heavy smokers at supplemental dose levels of beta-carotene varying from 6–15 mg/day for about 5 up to 7 years.

Accordingly, European Food Safety Authority (EFSA) concluded that exposure to beta-carotene from its use as food additive and as food supplement at a level below 15 mg/day do not give rise to concerns about adverse health effects in the general population, including heavy smokers.14

 

Flavonoids are a broad class of plant and fungus metabolites. They are an integral part of the human diet and are found in almost all fruits and vegetables. Along with carotenoids, they are responsible for the vivid colors in fruits and vegetables. They can act as an antioxidant or as a modulator of enzyme activity.1

Chemically they are a subclass of polyphenols, and may be the most abundant dietary antioxidants, with total intake of 1 gram or more per day. This is much higher than all other classes of phytochemicals and known dietary antioxidants. Our everyday polyphenols intake may be approximately 10 times higher than that of vitamin C and 100 times higher than that of vitamin E and carotenoids.35, 36

It should be noted that, according to Linus Pauling Institute and the European Food Safety Authority, the bioavailability of flavonoids is low due to limited absorption, extensive metabolism, and rapid excretion. Thus, their systemic antioxidant activity and their relative contribution to the antioxidant network might be small.21, 22, 23, 37, 38, 39, 40

Given the wide variability in structures within different flavonoids, it is difficult to generalize the absorbability and bioavailability of them based only on their structural classification.

The protective role of flavonoids in the diet of humans and their possible role in the prevention of various chronic and age-related diseases has been indicated in some large prospective studies.1

A recent meta-analysis of 14 individual studies published between 1996 and 2012 reported that higher intakes in each flavonoid subclass were significantly associated with a reduced risk of cardiovascular events.41, 40 In other meta-analyses, researchers found that flavonoid intake was inversely related to risk of stroke, diabetes, neurodegenerative diseases. 40, 42, 43, 44 Various flavonoids have been found to inhibit the development of chemically-induced cancers in animals, including lung, oral, esophageal, gastric, colon, skin, prostate, and mammary cancer. 40, 45,

 

Selenium and Zinc also participate in the antioxidant defense system of the body. Selenium’s role as an indirect component of the antioxidant network is well established. Various antioxidant enzymes (selenoenzymes) are selenium-dependent. 25 Zinc is a co-factor of the antioxidant enzyme SOD (copper/zinc-superoxide dismutase) involved in antioxidant defense systems, and protects the vascular and immunological systems from the damaging effects of free radicals. It is also a co-factor of over 300 mammalian proteins which may have a role in the prevention of initiation and progression of cancer.1, 24

Epidemiological findings have linked both a lowered selenium status, as well as zinc deficiency to neurodegenerative and cardiovascular diseases, and an increased risk of several types of cancer.1

Thiamine (Vitamin B1) and Riboflavin (Vitamin B2) also serve as a co-factor for several enzyme participants in our antioxidant defense. Riboflavin is involved in a range of redox reactions through the co-factors flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD). These act as electron carriers, and also serve as a coenzyme for glutathione reductase and other enzymes. 1, 26 Thiamine also serves as a co-factor for several enzymes, which are important in the biosynthesis of reducing equivalents used in oxidant stress defenses.

Coenzyme Q10 (Ubiquinone) is fat-soluble compound that is synthesized by the body and can be obtained from the diet. It plays a central role in cellular energy production, and also functions as an antioxidant in cell membranes and lipoproteins. It has been postulated that endogenous synthesis and dietary intake provide sufficient coenzyme Q10 to prevent deficiency in healthy people, but its concentrations in human tissues decline with age.

There is limited evidence to suggest that coenzyme Q10 supplementation prolongs life, and prevents age-related functional decline. A couple of studies (including a 12-year follow-up study) found that a combination of selenium and coenzyme Q10 supplementation may improve vitality, physical performance, and quality of life. In addition, a reduction in cardiovascular mortality with supplemental selenium and coenzyme Q10 was shown, compared to placebo.87, 88, 89

Melatonin is a hormone synthesized mainly in the pineal gland. Its main function is the regulation of our sleep-wake cycle, but it has many effects on a wide range of physiopathological functions. Melatonin is a potent free radical scavenger and thus it has the potential to play an important role in the reduction of free radical mediated diseases. Its levels decline with age and patients with neurodegenerative diseases have significant reduced of melatonin.1-10

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