The Ultimate Guide to Antioxidants
Antioxidants are, without a doubt, an essential part of optimal health. Even conventional Western physicians now acknowledge the significance of getting sufficient antioxidants from your diet or taking high-quality antioxidant supplements. But do you know how antioxidants function in your body and what types you need?
I have compiled all the basic facts about antioxidants to broaden your understanding of these nutrients, for you to better appreciate their importance in keeping you youthful and healthy.
What Are Antioxidants?
Antioxidants are a class of molecules that are capable of inhibiting the oxidation of another molecule. Your body naturally circulates various nutrients in your body due to their antioxidant properties. It also manufactures antioxidant enzymes in order to control free radical chain reactions. Some antioxidants are produced by your body, but
some are not. In addition, your body’s natural antioxidant production can decline as you age. Antioxidants play a significant role in your health, as they can control how fast you age by fighting free radicals.
The Health Benefits of Antioxidants: How Do They Prevent Free Radical Damage?
In order to fully understand how antioxidants truly benefit your well being, you should first be familiar with free radical formation.Biogerontologist Denham Harman was the first to discover the concept of free radicals in 1954, while researching an explanation for aging. Free radicals are a type of a highly reactive metabolite that is naturally produced by your body as a result of normal metabolism and energy production. They are your natural biological response to environmental toxins like cigarette smoke, sunlight, chemicals, cosmic and manmade radiation, and are even a key feature of pharmaceutical drugs. Your body also produces free radicals when you exercise and when you have inflammation anywhere in your body.
Free radical molecules are missing one or more electrons, and this missing electron is responsible
for biological oxidation. The incomplete molecules aggressively attack other molecules in order to replace their missing parts. These reactions are called “oxidation” reactions. Oxidation is called “biological rusting,” an effect
caused by too much oxygen in your tissues.
Free radicals steal electrons from the proteins in your body, which badly damages your DNA and other cell structures. They can create a “snowballing effect” – as molecules steal from one another, each one becomes a new free radical, leaving a trail of biological carnage.
Free radicals tend to collect in cell membranes (lipid peroxidation), which makes the cell lipids prone to oxidative damage. When this happens, the cell membrane becomes brittle and leaky, causing the cell to eventually fall apart and die. Free radicals can severely affect your DNA by disrupting the duplication of DNA, interfering with DNA
maintenance and breaking open or altering its structure by reacting with the DNA bases. Free radicals are linked
to over 60 different diseases, including: Cancer, Parkinson’s disease, Alzheimer’s disease, Cataracts and Atherosclerosis.
If your body does not get adequate protection, free radicals can become rampant, causing your cells to perform poorly. This can lead to tissue degradation and put you at risk of diseases.
This is where antioxidants come in.
Antioxidants are electron donors. They can break the free radical chain reaction by sacrificing their own
electrons to feed free radicals, but without turning into free radicals themselves.
Antioxidants are nature’s way of providing your cells with adequate defense against attack by reactive oxygen
species (ROS). As long as you have these important micronutrients, your body will be able to resist aging
caused by your everyday exposure to pollutants. If you don’t have an adequate supply of antioxidants to help
squelch free radicals, then you can be at risk of oxidative stress, which leads to accelerated tissue and organ
damage.
Numerous studies have confirmed the benefits of antioxidants and the role they play in maintaining good health
and reducing your risk of heart disease, Parkinson’s, Alzheimer’s, and cancer.
Antioxidants also help slow down the aging process, which can have immense effects on your skin health.
Other important benefits of antioxidants include:
Repairing damaged molecules – Some unique types of antioxidants can repair damaged molecules by donating a hydrogen atom. This is very important when the molecule is a critical one, like your DNA. Blocking metal radical
production – Some antioxidants have a chelating effect – they can grab toxic metals like mercury and arsenic,
which can cause free radical formation, and “hug” them so strongly to prevent any chemical reaction from taking place. Water-soluble chelating agents can also escort toxic metals out of your body through your urine.
Stimulating gene expression and endogenous antioxidant production – Some antioxidants can stimulate your
body’s genes and increase your natural defenses.
Providing a “shield effect” – Antioxidants, such as flavonoids, can act as a virtual shield by attaching to your DNA
to protect it from free radicals attacks.
Promoting cancer cells to “commit suicide” – Some antioxidants can provide anti-cancer chemicals that halt
cancer growth and force some cancer cells to self-destruct (apoptosis).
In his book The Antioxidants, Richard A. Passwater, PhD, says that humans have one of the longest natural lifespans in the animal kingdom, most likely because of the wealth of antioxidants in our omnivorous diet. Human
bodies also produce antioxidant enzymes that cannot be found in other creatures. “Our natural antioxidant
processes compensate for one another, covering up momentary deficiencies by their overlap.” Dr. Passwater says.
Many people think that taking just a few antioxidants – just one or two megadoses – is sufficient to maintain optimal health. But I strongly disagree. Instead, you must get a wide variety of antioxidants to maintain your wellbeing.
Different Types of Antioxidants:
The science of antioxidants can be quite complex, and this often leads to confusion among people on which types they should be taking. In fact, I’ve been asked several times whether it’s necessary to take astaxanthin(애스타크산틴,해초에서 얻는 초강력 항산화제) if you’re already taking a resveratrol supplement. The answer is YES – astaxanthin is actually a lipid-soluble antioxidant, while resveratrol is a water-soluble antioxidant. Each type of antioxidant has its own special function.
When classified according to their solubility, antioxidants can be categorized as either soluble in lipids/fat (hydrophobic) or water (hydrophilic). Both of these are required by your body in order to protect your cells, since the interior of your cells and the fluid between them are composed of water, while the cell membranes themselves are mostly made of fat. Since free radicals can strike either the watery cell contents or the fatty cellular membrane,
you need both types of antioxidants to ensure full protection from oxidative damage. Lipid-soluble antioxidants
are the ones that protect your cell membranes from lipid peroxidation. They are mostly located in your cell
membranes. Some examples of lipid-soluble antioxidants are vitamins A and E, carotenoids, and lipoic acid.
Water-soluble antioxidants are found in aqueous fluids, like your blood and the fluids within and around your cells (cytosol or cytoplasmic matrix). Some examples of water-soluble antioxidants are vitamin C, polyphenols, and glutathione.
However, solubility is not the only way to categorize antioxidants. They can also be categorized as enzymatic and non-enzymatic antioxidants.
Enzymatic antioxidants benefit you by breaking down and removing free radicals. They can flush out dangerous
oxidative products by converting them into hydrogen peroxide, then into water. This is done through a multi-step process that requires a number of trace metal cofactors, such as zinc, copper, manganese, and iron. Enzymatic antioxidants cannot be found in supplements, but instead are produced in your body.
The main enzymatic antioxidants in your body are:
Superoxide dismutase (SOD,슈퍼산화불균등화 효소) can break down superoxide into hydrogen peroxide and oxygen, with the help of copper, zinc, manganese, and iron. It is found in almost all aerobic cells and extracellular
fluids. Catalase (CAT) works by converting hydrogen peroxide into water and oxygen, using iron and manganese cofactors. It finishes up the detoxification process started by SOD.
Glutathione peroxidase (GSHpx) and glutathione reductase are selenium-containing enzymes that help break down hydrogen peroxide and organic peroxides into alcohols. They are most abundant in your liver.
Non-enzymatic antioxidants benefit you by interrupting free radical chain reactions. Some examples are carotenoids, vitamin C, vitamin E, plant polyphenols, and glutathione (GSH). Most antioxidants found in supplements and foods are non-enzymatic, and they provide support to enzymatic antioxidants by doing a “first sweep” and disarming the free radicals. This helps prevent your enzymatic antioxidants from being depleted.
Antioxidants can also be classified in terms of their molecular size:
Small-molecule antioxidants work by mopping up or “scavenging” the reactive oxygen species and carrying them away through chemical neutralization. The main players in this category are vitamins C and E, glutathione, lipoic acid, carotenoids, and CoQ10.
Large-protein antioxidants tend to be the enzymatic enzymes outlined above, as well as “sacrificial proteins,” that absorb ROS and stop them from attacking your essential proteins. One example of these sacrificial proteins is albumin, which “take the bullet” for crucial enzymes and DNA.
Isn’t it wonderful how nature has equipped you with the perfect combination of different defenses to cover almost every possible biological contingency?
Antioxidants You Should Not Miss Out On
As mentioned, it is crucial that you DO NOT stick to getting just one or two types of antioxidants. You need a wide array of antioxidants to provide you with optimal benefits.
Some antioxidants can be produced by your body. These are:
Glutathione – Known as your body’s most powerful antioxidant, glutathione is a tripeptide found in every single cell in your body. It is called “master antioxidant” because it is intracellular and has the unique ability of maximizing the performance of all the other antioxidants, including vitamins C and E, CoQ10, alpha-lipoic acid, as well as the fresh vegetables and fruits that you eat every day. Glutathione’s primary function is to protect your cells and mitochondria from oxidative and peroxidative damage. It is also essential for detoxification, energy utilization, and preventing the diseases we associate with aging. Glutathione also eliminates toxins from your cells and gives protection from the damaging effects of radiation, chemicals, and environmental pollutants.
Your body’s ability to produce glutathione decreases with aging. However, there are nutrients that can promote glutathione production, such as high-quality whey protein, curcumin, raw dairy, eggs, and grass-fed meat.
Alpha-Lipoic Acid (ALA) – Aside from its free radical scavenging abilities, this powerful antioxidant is also a great modifier of gene expression to reduce inflammation; Very potent heavy metal chelator and an enhancer of insulin sensitivity. ALA is the only antioxidant that can be easily transported into your brain, which offers numerous benefits for people with brain diseases, like Alzheimer’s disease. ALA can also regenerate other antioxidants, like vitamins C and E and glutathione. This means that if your body has used up these antioxidants, ALA can help regenerate them.
CoQ10 (Ubiquinone) – Used by every cell in your body, CoQ10 is converted by your body to its reduced form, called ubiquinol, to maximize its benefits. CoQ10 has been the subject of thousands of studies. Aside from naturally protecting you from free radicals, it also: Helps produce more energy for your cells; Provides support for your heart health, immune system, and nervous system; Helps reduce the signs of normal aging; Helps maintain blood pressure levels within the normal range. If you’re under 25 years old, your body can convert CoQ10 to ubiquinol without any difficulty. However, when you get older, your body becomes more and more challenged to convert the oxidized CoQ10 to ubiquinol. Therefore, you may need to take a ubiquinol supplement.
There are antioxidants that cannot be manufactured inside your body, and must be obtained from antioxidant-rich foods or potent antioxidant supplements. These are: Grapes rich with reservatrol: Grapes contain high levels of resveratrol.
Resveratrol – Found in certain fruits like grapes, vegetables, cocoa, and red wine, this antioxidant can cross the blood-brain barrier, providing protection for your brain and nervous system.
Resveratrol has been found to be so effective at warding off aging-related diseases that it was dubbed the “fountain of youth.”
Aside from providing free radical protection, this antioxidant can help: Inhibit the spread of cancer, especially prostate cancer; Lower your blood pressure; Keep your heart healthy and improve elasticity of your blood vessels; Normalize your anti-inflammatory response; Prevent Alzheimer’s disease.
Vegetable antioxidants:
Carotenoids give foods their beautiful vibrant color. Carotenoids are a class of naturally-occurring pigments that have powerful antioxidant properties. They are the compounds that give foods their vibrant colors. There are over 700 naturally-occurring carotenoids, and right now, you probably have at least 10 different kinds circulating through your bloodstream. Carotenoids can be classified into two groups:
Carotenes contain no oxygen atoms. Some examples are lycopene (found in red tomatoes) and beta-carotene (found in orange carrots), which is converted by your body into vitamin A.
Xanthophylls contain oxygen atoms, and examples include lutein, canthaxanthin (the gold in chanterelle mushrooms), zeaxanthin, and astaxanthin. Zeaxanthin is the most common carotenoid that naturally exists in nature and is found in peppers, kiwi, maize, grapes, squash, and oranges.
Astaxanthin – Although it’s technically a carotenoid, I believe this antioxidant deserves its own special mention due to its superb nutritional advantage. Astaxanthin is a marine carotenoid produced by the microalgae Haematococcus pluvialis when its water supply dries up, to give itself protection from ultraviolet radiation.
Astaxanthin rich salmon. Wild Alaskan red salmon is a great source of astaxanthin.
I believe that astaxanthin is the most powerful carotenoid in terms of free radical scavenging. It is
65 times more powerful than vitamin C, 54 times more powerful than beta-carotene, and 14 times more powerful than vitamin E. Like resveratrol, it can also cross the blood-brain barrier, AND the blood-retinal barrier – something that beta-carotene and lycopene cannot do.
Astaxanthin is also more effective than other carotenoids at “singlet oxygen quenching,” a particular type of oxidation caused by sunlight and various organic materials. Astaxanthin is 550 times more powerful than vitamin E and 11 times more powerful than beta-carotene at neutralizing this singlet oxygen.
Astaxanthin is an antioxidant with wide ranging benefits, such as:
Supporting your immune function
Improving your cardiovascular health by reducing C-Reactive Proteins (CRP) and triglycerides, and increasing
beneficial HDL
Protecting your eyes from cataracts(백내장), macular degeneration(시력감퇴), and blindness
Protecting your brain from dementia and Alzheimer’s
Reducing your risk of different types of cancer
Promoting recovery from spinal cord and other central nervous system injuries
Reducing inflammation from all causes, including arthritis and asthma
Improving your endurance, workout performance, and recovery
Relieving indigestion and reflux
Helping stabilize your blood sugar, thereby protecting your kidneys
Increasing sperm strength and sperm count and improving fertility
Helping prevent sunburn and protecting you from damaging radiation effects
Reducing oxidative damage to your DNA
Reducing symptoms of diseases, such as pancreatitis, multiple sclerosis, carpal tunnel syndrome, rheumatoid arthritis, Lou Gehrig’s disease, Parkinson’s disease, and neurodegenerative diseases
To learn more about this antioxidant’s benefits, I recommend reading
“Astaxanthin—Nature’s Most Powerful Antioxidant.”
Vitamin C – Dubbed the “grandfather” of the traditional antioxidants, vitamin C has a wide range of astonishing health benefits. As an antioxidant, vitamin C can help:
Battle oxidation by acting as a major electron donor; Maintain optimal electron flow in your cells; Protect proteins, lipids, and other vital molecular elements in your body.
Vitamin C is also essential for collagen synthesis, which is an important structural component of your bones, blood vessels, tendons, and ligaments.
You can get vitamin C from raw, organic vegetables and fruits, but you can also take it as a supplement or have it administered intravenously (IV). Personally, I am not fond of traditional vitamin C antioxidant supplements in the market, as they are not as bioavailable as they claim to be. When taking a vitamin C supplement, opt for one made with liposomal technology, which makes the nutrient more absorbable to your cells.
Vitamin E – Natural vitamin E is a family of eight different compounds: four tocopherols and four tocotrienols. You can obtain all these vitamin E compounds from a balanced diet composed of wholesome foods. However, if you take a synthetic vitamin E supplement, you will only get one of the eight compounds.
Antioxidant Food Sources
I believe that when it comes to obtaining nutrients, your diet – not supplements – should be your primary source. If you consume a balanced, unprocessed diet that’s full of high-quality, raw organic foods, especially fruits and vegetables, your body will acquire the essential nutrients and antioxidants it requires to achieve or maintain optimal health.
What are the best antioxidant-rich foods you should have in your diet? Some of my top recommendations are:
Fresh, organic vegetables. Most of the vegetables you eat, especially the green leafy ones, are loaded with potent phytochemicals, which are plant compounds that act as antioxidants. Phytochemicals can reduce inflammation and eliminate carcinogens. However, to maximize the antioxidants in vegetables, you must consume them raw, in a state closest to when they were harvested. I highly recommend juicing for you to absorb all the nutrients in the vegetables – it is one of the healthiest antioxidant drinks you can add to your diet. You may also eat the pulp instead of throwing it away. For valuable tips in vegetable juicing, read my article “Benefits of Juicing: Your Keys to Radiant Health.”
Sprouts are also powerful sources of antioxidants, minerals, vitamins, and enzymes that promote optimal health. My two favorites are pea and sunflower sprouts, as they provide you with the highest-quality protein you can eat. I used to grow sprouts in Ball jars over 10 years ago, but I stopped doing it and switched to growing them in trays instead. I now consume one whole tray of sprouts every two to three days.
Fruits. Fresh berries like blueberries, blackberries, cranberries, and raspberries are the best antioxidant fruits you can consume, as they contain powerful phytochemicals that directly inhibit the DNA binding of certain carcinogens. Berries are also great sources of antioxidants like vitamin C, carotenes, and carotenoids, as well as nutrients like zinc, potassium, iron, calcium, and magnesium. However, I advise consuming fruits in moderation, as they contain fructose, which can be detrimental to your health in high amounts.
Nuts: Pecans, walnuts, and hazelnuts are excellent antioxidant foods that can boost your heart health and overall health. Look for nuts that are organic and raw, not irradiated or pasteurized. I do not recommend consuming peanuts, as they are usually pesticide-laden and can be contaminated with a carcinogenic mold called aflatoxin.
Herbs and spices. Aside from being an abundant source of antioxidants, these can have potential anti-cancer benefits. Herbs and spices differ mainly by source, as herbs typically come from the plant’s leaves while spices come from the bark, stem, and seeds. Both have been used for thousands of years to flavor foods and treat illness. Some of your best choices are ground cloves, ground cinnamon, oregano, turmeric, ginger, and garlic. Ideally, you should only opt for fresh herbs and spices, as they are healthier and have higher antioxidant levels than processed, powdered versions. For example, the antioxidant activity of fresh garlic is 1.5 times higher than dry garlic powder.
Organic green tea. This antioxidant-rich drink contains epigallocatechin-3-gallate (EGCG), a catechin polyphenol and one of the most powerful antioxidants known today. EGCG benefits you by lowering your risk of heart attack and stroke, glaucoma, high cholesterol, and more. Studies have also found that it can improve your exercise performance, increase fat oxidation, and even help prevent obesity due to its regulatory effect on fat metabolism. However, remember that not all green teas are created equal. Some processed green tea brands can contain very little or no EGCG at all. Some tea bags are also contaminated with fluoride or contain hazardous plastics that can leach into your tea when brewing.
To ensure you’re drinking high-quality green tea, I advise buying only organic, loose leaf tea from a reputable source. My top tea choices are organic matcha tea and tulsi tea.
I also recommend consuming high-quality whey protein – cold-pressed, derived from grass-fed cows, and free of hormones, sugar, and chemicals.
Whey protein provides all the essential key amino acids for glutathione antioxidant production: cysteine, glycine, and glutamate. It also contains glutamylcysteine, a unique cysteine residue that’s highly bioactive in its affinity for converting to glutathione. The scientists at the US Department of Agriculture (USDA) have created a scale for measuring an antioxidant food’s or supplement’s ability to neutralize free radicals, called the Oxygen Radical Absorbance Capacity (ORAC) score. The higher a food’s ORAC score, the more powerful it is in fighting age-related degeneration and disease. You can go to the ORAC values database if you want to look up your food or supplement’s ORAC score. But be warned: some manufacturers are using deceptive practices to misrepresent ORAC values and deceive consumers.
Recommended Antioxidant Supplements
As many of you know, I do not recommend taking many supplements, as they cannot replace the nutrients and benefits you can get from whole organic foods. Supplements should only be taken to supplement your diet, and not to completely replace it. However, due to today’s fast-paced and busy lifestyle, many people are now neglecting the importance of consuming whole, organic foods. They do not have time to cook and prepare wholesome meals, causing them to miss out on essential nutrients, including antioxidants.
In this case, taking a high-quality antioxidant supplement may be an ideal option. Some of my personal recommendations are: Astaxanthin with ALA, Krill Oil, Purple Defense, Acai Berry,
Vitamin E, Liposomal Vitamin C, CoQ10/Ubiquinol
However, remember that overloading on antioxidants, especially from supplements, can have negative effects on your health. It can be easy to overdose when taking antioxidants supplements, so always remember
the Goldilocks equation: not too many, but not too few.
Lifestyle Changes to Maximize Your Antioxidant Intake
An antioxidant-rich diet will not work to your advantage if you do not combine it with a healthy lifestyle. Remember, there are unhealthy lifestyle habits that can promote free radical formation. Fail to put a stop to these and the levels of free radicals in your body can rise to dangerous levels, putting you at risk of inflammation and paving the way for disease and illness.
Aside from consuming a wholesome diet, here are a few lifestyle pointers I highly recommend:
Reduce and eventually eliminate sugar (especially fructose) and grains from your diet. According to Dr. Robert Lustig, professor of pediatrics in the Division of Endocrinology at the University of California, San Francisco, fructose undergoes the Maillard reaction with proteins, which leads to superoxide free radicals to form in your body. These damaging free radicals can cause liver inflammation similar to that caused by alcohol. Less sugar and grains (which convert into sugar in your body) in your diet can help decrease your antioxidant stress, meaning you will need to get less amounts. Plus, the antioxidants you have will work better and last longer. I also advise against consuming any type of processed foods, especially soda, as these usually contain high amounts of fructose.
Exercise. Exercise can boost your body’s antioxidant production but in a paradoxical way, as it actually creates potent oxidative stress. However, if you do it properly and in moderation, it can help improve your body’s capacity to produce antioxidants. This is why I recommend doing short bursts of high-intensity exercises like Peak Fitness, instead of prolonged cardio like marathon running, which puts excessive stress on your heart.
Manage your stress. Stress can exacerbate the inflammation and poor immune function caused by free radical formation. Studies have found significant links between acute and/or chronic emotional and psychological stress and numerous health issues. Even the Centers for Disease Control (CDC) acknowledges this link, and says that 85 percent of all disease has an emotional element. To manage your stress effectively, I recommend using energy psychology tools, like the Emotional Freedom Technique (EFT). EFT is a form of psychological acupuncture – but without the needles – that can help you can correct the emotional short circuiting that contributes to your chronic stress.
Avoid smoking. Smoking forms free radicals in your body, which accelerates the aging process. Even being around people who smoke can affect your health by damaging the microcapillaries in your skin, which limits its ability to absorb nutrients, leading to accelerated wrinkling and aging. Smoking also contributes to the pathobiology of various diseases, the most well-known of which is lung cancer.
Get enough sleep. High-quality sleep is one of the cornerstones of good health, and science has now established that a sleep deficit can have severe far-reaching effects on your health. Six to eight hours of sleep per night seems to be the optimal amount for most adults, and too much or too little can have adverse effects on your wellbeing.
If you are having problems sleeping, I recommend reading my 33 Tips for a Good Night’s Sleep.
Try grounding. Also called “earthing,” grounding has a potent antioxidant effect that helps alleviate inflammation in your body. There is a constant flow of energy between our bodies and the earth, which has a greater negative charge. Walking barefoot on the earth helps you absorb large amounts of negative electrons through the soles of your feet.
The best way to incorporate grounding into your lifestyle is to exercise barefoot outdoors, such as on the beach or in your yard. It’s one of the most wonderful, inexpensive, and powerful ways to uplift your health.
Reactive oxygen species
Reactive oxygen species (ROS) are chemically reactive chemical speciesperoxides, superoxide, hydroxyl radical, and singlet oxygen[2]
In a biological context, ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis(([3] (항상성은 생명력과 직접적으로 관련된 기운)However, during times of environmental stress (e.g., UV[3] This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stressionizing radiation[4]
Formation and decompositionEdit
The reduction of molecular oxygen (O2) produces superoxide (•O−
2) and is the precursor of most other reactive oxygen species:[5]
- O2 + e− → •O−
2
Dismutation of superoxide produces hydrogen peroxide (H2O2):[5]
- 2 H+ + •O−
2 + •O−
2 → H2O2 + O2
Hydrogen peroxide in turn may be partially reduced to hydroxyl radical (•OH) or fully reduced to water:[5]
- H2O2 + e− → HO− + •OH
- 2 H+ + 2 e− + H2O2 → 2 H2O
Exogenous ROSEdit
Exogenous ROS can be produced from pollutants, tobacco, smoke, drugs, xenobiotics
Ionizing radiation can generate damaging intermediates through the interaction with water, a process termed radiolysishydroxyl radical (•OH), hydrogen peroxide (H2O2), superoxide radical (•O−
2) and ultimately oxygen (O2).
The hydroxyl radical is extremely reactive and immediately removes electrons from any molecule in its path,
turning that molecule into a free radical and thus propagating a chain reaction. However, hydrogen peroxide is actually more damaging to DNA than the hydroxyl radical, since the lower reactivity of hydrogen peroxide provides
enough time for the molecule to travel into the nucleus of the cell, subsequently reacting with macromolecules such as DNA.
Endogenous ROSEdit
ROS are produced intracellularly through multiple mechanisms and depending on the cell and tissue types, the major sources being the "professional" producers of ROS: NADPH oxidase[6][7] Mitochondria convert energy for the cell into a usable form, adenosine triphosphateoxidative phosphorylation, involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane by means of the electron transport chainproteinssuperoxide radical (•O−
2), most well documented for Complex I and Complex III[8] Superoxide is not particularly reactive by itself, but can inactivate specific enzymes or initiate lipid peroxidation in its protonated form, hydroperoxyl HO•
2. The pKa of hydroperoxyl is 4.8. Thus, at physiological pH, the majority will exist as superoxide anion.
If too much damage is present in mitochondria, a cell undergoes apoptosisapoptosomesphagocytosis
Superoxide dismutaseEdit
Superoxide dismutasesantioxidant
The SOD-catalysed dismutation of superoxide
- M(n+1)+ − SOD + O−
2 → Mn+ − SOD + O2 - Mn+ − SOD + O−
2 + 2H+ → M(n+1)+ − SOD + H2O2.
where M = Cu (n = 1); Mn (n = 2); Fe (n = 2); Ni (n = 2). In this reaction the oxidation state of the metal cation oscillates between n and n + 1.
Catalase, which is concentrated in peroxisomesGlutathione peroxidaseglutathionePeroxiredoxins also degrade H2O2, within the mitochondria, cytosol, and nucleus.
- 2 H2O2 → 2 H2O + O2 (catalase)
- 2GSH + H2O2 → GS–SG + 2H2O (glutathione peroxidase)
Singlet oxygenEdit
Another type of reactive oxygen species is singlet oxygen (1O2) which is produced for example as byproduct of photosynthesisphotosensitizers such as chlorophyll may convert triplet (3O2) to singlet oxygen:[9]
Singlet oxygen is highly reactive, especially with organic compounds that contain double bonds. The resulting damage caused by singlet oxygen reduces the photosynthetic efficiency of chloroplasts[9] Various substances such as carotenoids, tocopherols and plastoquinonessignaling[9] Oxidized products of β-carotene arising from the presence of singlet oxygen act as second messengersjasmonate[9]
Damaging effectsEdit
Effects of ROS on cell metabolism are well documented in a variety of species. These include not only roles in apoptosis (programmed cell death) but also positive effects such as the induction of host defence[10][11]genes[citation needed] This implicates them in control of cellular function. In particular, platelets involved in wound repair
and blood homeostasis release ROS to recruit additional platelets to sites of injury immune system via the recruitment of leukocytes[citation needed]
Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including
cardiovascular disease hearing impairment via cochlear damage induced by elevated sound levels, in ototoxicity of drugs such as cisplatin[citation needed] ROS are also implicated in mediation of apoptosis or programmed cell death and ischaemicstroke and heart attack[citation needed]
In general, harmful effects of reactive oxygen species on the cell are most often:[12]
- damage of DNA or RNA
- oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
- oxidations of amino acids in proteins
- oxidative deactivation of specific enzymes by oxidation of co-factors
Pathogen responseEdit
When a plant recognizes an attacking pathogen, one of the first induced reactions is to rapidly produce superoxide (O−
2) or hydrogen peroxide (H
2O
2) to strengthen the cell wall. This prevents the spread of the pathogen to other parts of the plant, essentially forming a net around the pathogen to restrict movement and reproduction.
In the mammalian host, ROS is induced as an antimicrobial defense. To highlight the importance of this defense, individuals with chronic granulomatous disease who have deficiencies in generating ROS, are highly susceptible to infection by a broad range of microbes including Salmonella enterica, Staphylococcus aureus, Serratia marcescens, and Aspergillus spp.
The exact manner in which ROS defends the host from invading microbe is not fully understood. One of the more likely modes of defense is damage to microbial DNA. Studies using Salmonella demonstrated that DNA repair mechanisms were required to resist killing by ROS. More recently, a role for ROS in antiviral defense mechanisms has been demonstrated via Rig-like helicase-1 and mitochondrial antiviral signaling protein. Increased levels of ROS potentiate signaling through this mitochondria-associated antiviral receptor to activate interferon regulatory factor (IRF)-3, IRF-7, and nuclear factor kappa B (NF-κB), resulting in an antiviral state.[13] Respiratory epithelial cells were recently demonstrated to induce mitrochondrial ROS in response to influenza infection. This induction of ROS led to the induction of type III interferon and the induction of an antiviral state, limiting viral replication.[14] In host defense against mycobacteria, ROS play a role, although direct killing is likely not the key mechanism; rather, ROS likely affect ROS-dependent signalling controls, such as cytokine production, autophagy, and granuloma formation.[15]
Reactive oxygen species are also implicated in activation, anergy and apoptosis of T cells[16]
Oxidative damageEdit
In aerobic organisms the energy needed to fuel biological functions is produced in the mitochondria via the electron transport chaincellularDNA, RNA, and proteins, which, in theory, contributes to the physiology of aging
ROS are produced as a normal product of cellular metabolismhydrogen peroxide (H2O2), which is converted from superoxideCatalase and superoxide dismutase ameliorate the damaging effects of hydrogen peroxide and superoxide, respectively, by converting these compounds into oxygen and hydrogen peroxide (which is later converted to water), resulting in the production of benign molecules[17] Memory capabilities decline with age, evident in human degenerative diseases such as Alzheimer's diseasefitnessmetabolites and then given cognitive testsrats[18] Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production.[19] The accumulation of oxidative damage and its implications for aging depends on the particular tissuebraingerbilsmice with a spin trapping[20]
Cause of agingEdit
According to the Free-radical theory Drosophila do show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes). Also contrary to this theory, deletion of mitochondrial SOD2 can extend lifespan in Caenorhabditis elegans.[21]
In mice, the story is somewhat similar. Deleting antioxidant enzymes, in general, yields shorter lifespan, though
overexpression studies have not (with some recent exceptions) consistently extended lifespan.[22] Study of a rat model of premature aging found increased oxidative stress, reduced antioxidant enzyme activity and substantially greater DNA damage in the brain neocortex and hippocampus[23] The DNA damage 8-OHdG8-OHdG increases in different mammalian organs with age[24] (see DNA damage theory of aging
Male infertilityEdit
Exposure of spermatozoa to oxidative stress is a major causative agent of male infertility[25] Sperm DNA fragmentation[26] A high level of the oxidative DNA damage 8-OHdG[27]
CancerEdit
ROS are constantly generated and eliminated in the biological system and are required to drive regulatory pathways.[28] Under normal physiological conditions, cells control ROS levels by balancing the generation of ROS with their elimination by scavenging system. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids and DNA, leading to fatal lesions in cell that contribute to carcinogenesis.
Cancer cells exhibit greater ROS stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction. ROS is a double-edged sword. On one hand, at low levels, ROS facilitates cancer cell survival since cell-cycle progression driven by growth factors and receptor tyrosine kinases (RTK) require ROS for activation[29] and chronic inflammation, a major mediator of cancer, is regulated by ROS. On the other hand, a high level of ROS can suppress tumor growth through the sustained activation of cell-cycle inhibitor[30][31] and induction of cell death as well as senescence by damaging macromolecules. In fact, most of the chemotherapeutic and radiotherapeutic agents kill cancer cells by augmenting ROS stress.[32][33] The ability of cancer cells to distinguish between ROS as a survival or apoptotic signal is controlled by the dosage, duration, type, and site of ROS production. Modest levels of ROS are required for cancer cells to survive, whereas excessive levels kill them.
Metabolic adaptation in tumours balances the cells' need for energy with equally important need
for macromolecular building blocks and tighter control of redox balance. As a result, production of NADPH[34]
Most risk factors associated with cancer interact with cells through the generation of ROS. ROS then activate various transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), hypoxia-inducible factor-1α and signal transducer and activator of transcription 3 (STAT3), leading to expression of proteins that control inflammation; cellular transformation; tumor cell survival; tumor cell proliferation; and invasion, agiogenesis as well as metastasis. And ROS also control the expression of various tumor suppressor genes such as p53, retinoblastoma gene (Rb), and phosphatase and tensin homolog (PTEN).[35]
CarcinogenesisEdit
ROS-related oxidation of DNA is one of the main causes of mutations, which can produce several types of DNA damage, including non-bulky (8-oxoguanine and formamidopyrimidine) and bulky (cyclopurine and etheno adducts) base modifications, abasic sites, non-conventional single-strand breaks, protein-DNA adducts, and intra/interstrand DNA crosslinks.[36] It has been estimated that endogenous ROS produced via normal cell metabolism modify approximately 20,000 bases of DNA per day in a single cell. 8-oxoguanine is the most abundant among various oxidized nitrogeneous bases observed. During DNA replication, DNA polymerase mispairs 8-oxoguanine with adenine, leading to a G→T transversion mutation. The resulting genomic instability directly contributes to carcinogenesis. Cellular transformation leads to cancer and interaction of atypical PKC-ζ isoform with p47phox controls ROS production and transformation from apoptotic cancer stem cells through blebbishield emergency program[37][38]
Cell proliferationEdit
Uncontrolled proliferation is a hallmark of cancer cells. Both exogenous and endogenous ROS have been shown to enhance proliferation of cancer cells. The role of ROS in promoting tumor proliferation is further supported by the observation that agents with potential to inhibit ROS generation can also inhibit cancer cell proliferation.[35] Although ROS can promote tumor cell proliferation, a great increase in ROS has been associated with reduced cancer cell proliferation by induction of G2/M cell cycle arrest; increased phosphorylation of ataxia telangiectasia mutated (ATM), checkpoint kinase 1 (Chk 1), Chk 2; and reduced cell division cycle 25 homolog c (CDC25).[39]
Cell deathEdit
A cancer cell can die in three ways: apoptosis, necrosis and autophagy[40] In the extrinsic pathway of apoptosis, ROS are generated by Fas ligand as an upstream event for Fas activation via phosphorylation, which is necessary for subsequent recruitment of Fas-associated protein with death domain and caspase 8 as well as apoptosis induction.[35] In the intrinsic pathway, ROS function to facilitate cytochrome c release by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as inhibiting pore-destabilizing proteins (Bcl-2-associated X protein, Bcl-2 homologous antagonist/killer).[41] The intrinsic pathway is also known as the caspase cascade and is induced through mitochondrial damage which triggers the release of cytochrome c. DNA damage, oxidative stress, and loss of mitochondrial membrane potential lead to the release of the pro-apoptotic proteins mentioned above stimulating apoptosis.[42] Mitochondrial damage is closely linked to apoptosis and since mitochondria are easily targeted there is potential for cancer therapy.[43]
The cytotoxic nature of ROS is a driving force behind apoptosis, but in even higher amounts, ROS can result in both apoptosis and necrosis, a form of uncontrolled cell death, in cancer cells.[44]
Numerous studies have shown the pathways and associations between ROS levels and apoptosis, but a newer line of study has connected ROS levels and autophagy.[45] ROS can also induce cell death through autophagy, which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted or damaged organelles and protein aggregates) for degradation in lysosomes.[46] Therefore, autophagy can also regulate the cell’s health in times of oxidative stress. Autophagy can be induced by ROS levels through many different pathways in the cell in an attempt to dispose of harmful organelles and prevent damage, such as carcinogens, without inducing apoptosis.[47] Autophagic cell death can be prompted by the over expression of autophagy where the cell digests too much of itself in an attempt to minimize the damage and can no longer survive. When this type of cell death occurs, an increase or loss of control of autophagy regulating genes is commonly co-observed.[48] Thus, once a more in-depth understanding of autophagic cell death is attained and its relation to ROS, this form of programmed cell death may serve as a future cancer therapy. Autophagy and apoptosis are two different cell death mechanisms brought on by high levels of ROS in the cells, however; autophagy and apoptosis rarely act through strictly independent pathways. There is a clear connection between ROS and autophagy and a correlation seen between excessive amounts of ROS leading to apoptosis.[47] The depolarization of the mitochondrial membrane is also characteristic of the initiation of autophagy. When mitochondria are damaged and begin to release ROS, autophagy is initiated to dispose of the damaging organelle. If a drug targets mitochondria and creates ROS, autophagy may dispose of so many mitochondria and other damaged organelles that the cell is no longer viable. The extensive amount of ROS and mitochondrial damage may also signal for apoptosis. The balance of autophagy within the cell and the crosstalk between autophagy and apoptosis mediated by ROS is crucial for a cell’s survival. This crosstalk and connection between autophagy and apoptosis could be a mechanism targeted by cancer therapies or used in combination therapies for highly resistant cancers.
Tumor cell invasion, angiogenesis and metastasisEdit
After growth factor stimulation of RTKs, ROS can trigger activation of signaling pathways involved in cell migration and invasion such as members of the mitogen activated protein kinase (MAPK) family – extracellular regulated kinase (ERK), c-jun NH-2 terminal kinase (JNK) and p38 MAPK. ROS can also promote migration by augmenting phosphorylation of the focal adhesion kinase (FAK) p130Cas and paxilin.[49]
Both in vitro and in vivo, ROS have been shown to induce transcription factors and modulate signaling molecules involved in angiogenesis (MMP, VEGF) and metastasis (upregulation of AP-1, CXCR4, AKT and downregulation of PTEN).[35]
Chronic inflammation and cancerEdit
Experimental and epidemiologic research over the past several years has indicated close associations among ROS, chronic inflammation, and cancer.[35] ROS induces chronic inflammation by the induction of COX-2, inflammatory cytokines (TNFα, interleukin 1 (IL-1), IL-6), chemokines (IL-8, CXCR4) and pro-inflammatory transcription factors (NF-κB).[35] These chemokines and chemokine receptors, in turn, promote invasion and metastasis of various tumor types.
Cancer therapyEdit
Both ROS-elevating and ROS-eliminating strategies have been developed with the former being predominantly used. Cancer cells with elevated ROS levels depend heavily on the antioxidant defense system. ROS-elevating drugs further increase cellular ROS stress level, either by direct ROS-generation (e.g. motexafin gadolinium, elesclomol) or by agents that abrogate the inherent antioxidant system such as SOD inhibitor (e.g. ATN-224, 2-methoxyestradiol) and GSH inhibitor (e.g. PEITC, buthionine sulfoximine (BSO)). The result is an overall increase in endogenous ROS, which when above a cellular tolerability threshold, may induce cell death.[50][51] On the other hand, normal cells appear to have, under lower basal stress and reserve, a higher capacity to cope with additional ROS-generating insults than cancer cells do.[50][52] Therefore, the elevation of ROS in all cells can be used to achieve the selective killing of cancer cells.
Radiotherapy also relies on ROS toxicity to eradicate tumor cells. Radiotherapy uses X-rays, γ-rays as well as heavy particle radiation such as protons and neutrons to induce ROS-mediated cell death and mitotic failure.[35]
Due to the dual role of ROS, both prooxidant and antioxidant-based anticancer agents have been developed. However, modulation of ROS signaling alone seems not to be an ideal approach due to adaptation of cancer cells to ROS stress, redundant pathways for supporting cancer growth and toxicity from ROS-generating anticancer drugs. Combinations of ROS-generating drugs with pharmaceuticals that can break the redox adaptation could be a better strategy for enhancing cancer cell cytotoxicity.[35]
James Watson[53] and others[54] have proposed that lack of intracellular ROS due to a lack of physical exercise may contribute to the malignant progression of cancer, because spikes of ROS are needed to correctly fold proteins in the endoplasmatic reticulum and low ROS levels may thus aspecifically hamper the formation of tumor suppressor proteins.[54] Since physical exercise induces temporary spikes of ROS, this may explain why physical exercise is beneficial for cancer patient prognosis.[55] Moreover, high inducers of ROS such as 2-deoxy-D-glucose and carbohydrate-based inducers of cellular stress induce cancer cell death more potently because they exploit cancer cell high avidity for sugars.[56]
See alsoEdit
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Further readingEdit
- Sen CK (2003). "The general case for redox control of wound repair". Wound Repair and Regeneration. 11 (6): 431–8. doi:10.1046/j.1524-475X.2003.11607.xPMID 14617282
- Krötz F, Sohn HY, Gloe T, Zahler S, Riexinger T, Schiele TM, Becker BF, Theisen K, Klauss V, Pohl U (August 2002). "NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment". Blood. 100 (3): 917–24. doi:10.1182/blood.V100.3.917PMID 12130503
- Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F (January 1998). "Hydrogen peroxide is involved in collagen-induced platelet activation". Blood. 91 (2): 484–90. PMID 9427701
- Guzik TJ, Korbut R, Adamek-Guzik T (December 2003). "Nitric oxide and superoxide in inflammation and immune regulation". Journal of Physiology and Pharmacology. 54 (4): 469–87. PMID 14726604
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