- Free radicals, antioxidants and functional foods: Impact on human health
- Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases
- What is Oxidative Stress? The Health Impact of Free Radicals
- What Increases Free Radicals?
- “Free Radical Defense”
- Research Limitations
- Disease Associations
- Cellular Damage
- Cancer Controversy
- Natural Antioxidant Defense
- Antioxidant Supplements
- What Are Free Radicals?
- The danger of free radicals
- Symptoms of oxidative stress
- Testing for free radicals
- Antioxidants and free radicals
- Free radicals and exercise
- Natural Remedies for Fighting Oxidative Stress
Free radicals, antioxidants and functional foods: Impact on human health
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Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases
The average life expectancy has increased rapidly over the past decades, with an average of around 71.4 years in 2015 worldwide (World Health Organization, 2018).
In view of the demographics of the world population in between 2000 and 2050, the population over 60 years is expected to grow from 605 million to 2 billion people (World Health Organization, 2014). Although the increasing life expectancy reflects a positive human development, a new challenge is arising.
In fact, growing older is positively linked to cognitive and biological degeneration such as physical frailty, psychological impairment, and cognitive decline (Jin et al., 2015).
Age-related diseases have become the greatest health threats in the twenty-first century.
Aging is an intrinsic, universal, multifactorial, and progressive process characterized as degenerative in nature, accompanied by progressive loss of function and ultimately increased mortality rate (Dabhade and Kotwal, 2013; López-Otín et al., 2013; Shokolenko et al., 2014; Chang et al., 2017).
Among the theories that explain the aging process, the free radical theory of aging is long-established (Harman, 1956).
This theory speculates that aging is a consequence of the failure of several defensive mechanisms to respond to the reactive oxygen species (ROS)-induced damage, particularly at the mitochondria (Islam, 2017).
Age-related diseases are related to structural changes in mitochondria, accompanied by the alterations of biophysical properties of the membrane including alteration in the electron transport chain complexes activities, decreased fluidity, and subsequently resulted in energy imbalance and mitochondrial failure.
These perturbations impair cellular homeostasis and mitochondrial function and enhance vulnerability to oxidative stress (Eckmann et al., 2013; Chistiakov et al., 2014). Elderly people are susceptible to oxidative stress due to a decline in the efficiency of their endogenous antioxidant systems. Organs such as brain and heart, with high rates of oxygen consumption and limited respiration levels, are particularly vulnerable to this phenomenon, hence partially explaining the high prevalence of cardiovascular diseases (CVD) and neurological disorders in elderly (Corbi et al., 2008).
Oxidative stress plays a crucial role in the development of age-related diseases including arthritis, diabetes, dementia, cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, and metabolic syndromes (Tan et al., 2015a; Liu et al., 2017).
ROS are generated within the biological system to modulate the cellular activities such as cell survival, stressor responses, and inflammation (He and Zuo, 2015; Zuo et al., 2015). Elevation of ROS has been associated with the onset and progression of aging. Although ROS generation may not be an essential factor for aging (López-Otín et al.
, 2013), they are more ly to exacerbate age-related diseases progression via oxidative damage and interaction with mitochondria (Dias et al., 2013). Due to their reactivity, high concentrations of ROS can cause oxidative stress by disrupting the balance of antioxidant and prooxidant levels (Zuo et al., 2015).
Emerging research evidence has suggested that natural compounds can reduce oxidative stress and improve immune function (Ricordi et al., 2015). Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways.
Therefore, the role of molecules with antioxidant activity that promote healthy aging and counteract oxidative stress is worth to discuss further. Of particular interest in (II) ions and glutathione. RSC Adv. 6, 103169–103177. doi: 10.1039/C6RA21309J
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What is Oxidative Stress? The Health Impact of Free Radicals
One theory suggests that oxidative stress may underlie different diseases, including mental health and brain disorders, heart disease, diabetes, and more. Is there scientific ground to this theory and what exactly is oxidative stress? We go into the science behind it to explain how the body strikes a balance between free radicals and antioxidants to maintain good health.
Scientists commonly use the term “oxidative stress.” It refers to a relative dominance of free radicals over antioxidants. It means that more free radicals are being produced than can be neutralized or removed from the cells, tissues, or the body as a whole [1, 2].
To a certain extent, free radicals are normally produced in the body. They support immune defense and help cells communicate. But an excess of free radicals, such as from toxin exposure and pollution, may lead to tissue damage .
Reactive oxygen species (ROS) is an umbrella term for a variety of highly reactive molecules or oxidants. The most prominent members include superoxide (O2·−), hydroxyl (OH·), and peroxy radical (ROO). The mitochondria are their main production site [1, 3].
Reactive oxygen species (ROS) are produced by all cell types that line blood vessels, muscles, and connective tissue with the help of numerous enzymes. They are also produced by neutrophils and macrophages during inflammation, which is needed short-term to help the body fight off infections [4, 3].
The rate and magnitude of oxidant formation are usually balanced by the rate of oxidant elimination. Oxidative stress is when prooxidants override antioxidant defense .
What Increases Free Radicals?
Some research suggests that oxidants can also be generated by:
- Different types of radiation, with X-irradiation generating the hydroxyl radical [6, 3].
- Excess UV light [6, 3].
- Ultrasound and microwave radiation .
- Mineral excess or heavy metals (including iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel) .
- Pollutants .
“Free Radical Defense”
It has become apparent to scientists that plants actively produce ROS as a way to control processes such as programmed cell death, stress responses, defense against microbes and cellular communication .
Research suggests that we might use free radicals in a similar way.
That means that our bodies don’t only have “antioxidant defense,” as most people see it. We also seem to have “free radical defense.”
In humans, free radical reactions are essential for defense against microbes. Neutrophils, macrophages and other cells of the immune system produce them. However, their overproduction can have a counter-effect, leading to tissue injury and cell death .
ROS within cells act as communication molecules. In low concentrations, they appear to increase the growth, reproduction, and survival of cell types. In high concentrations, they may induce cell death. This is being researched as a potential cancer-fighting approach .
Researchers point to their other roles in the body, such as regulating cellular calcium, protein phosphorylation, and transcription factors – all of which are seen as crucially important for human health [3, 2].
The majority of studies covered in this section deal with associations only, which means that a cause-and-effect relationship hasn’t been established.
For example, just because heart disease has been linked with high oxidative stress doesn’t mean that heart disease is caused by oxidative stress. Data are lacking to make such claims.
Also, even if a study did find that free radicals can contribute to heart disease, they are highly unly to be the only cause. Complex disorders heart disease always involve multiple possible factors – including biochemistry, environment, health status, and genetics – that may vary from one person to another.
According to limited research, as many as 200 human diseases have been associated with increased levels of oxidative stress. These include the following :
- Cardiovascular disease , Stroke , Heart failure , Hypertension [9, 4]
- High cholesterol [9, 4]
- Cancer 
- Parkinson’s disease 
- Alzheimer’s disease 
- Diabetes 
- Kidney disease 
Some studies had conflicting findings. More research is needed.
Scientists found that high concentrations of ROS can damage structures within cells, including fats (in membranes), proteins, and nucleic acids that build RNA and DNA. What constitutes “high levels” in our day-to-day life has yet to be determined, though .
According to one hypothesis, oxidative damage accumulates during the life cycle, and it may play a role in the development of age-related diseases such as arthritis, dementia, and others. Although possible, large-scale evidence is still lacking to firmly establish this hypothesis [3, 2].
People with both type 1 and 2 diabetes seem to have high levels of free radicals, according to some estimates. The onset of diabetes has been associated with oxidative stress, but its exact role is still unclear .
Too much oxidative stress relevant to antioxidant levels is also hypothesized to impair sugar balance .
In one study, oxidative stress was suggested to accelerate diabetes complications by damaging proteins. Another study suggests that oxidative stress byproducts contribute to insulin resistance, a hallmark of type 2 diabetes. Large scale data are needed .
Oxidative stress damages and impairs the functioning of several kinds of proteins, harming the lungs in ways that can induce COPD, a chronic lung disease. The main cause of COPD is smoking, a major source of toxic chemicals and trigger of excess free radicals in the body .
The harmful effects of oxidative stress in COPD include excessive mucus, membrane damage, and lung cell death .
It may start off a vicious cycle in COPD patients: oxidative stress causes inflammation, and inflammation, in turn, causes more oxidative stress .
Scientists think this cycle is hard to break because oxidation makes various proteins lose function, and that hinders the body’s ability to restore a healthy oxidant/antioxidant balance .
The link between free radicals and cancer is still unclear.
Researchers explain that DNA mutation is a critical step in cancer formation. Excessive DNA damage caused by free radicals (as measured by 8-OH-G) has been found in tumors. One unproven hypothesis states that this type of damage may underlie cancer initiation, but solid evidence is lacking .
High levels of oxidative stress are toxic to cells and ultimately kill them. Thus, increasing oxidative stress has been studied as a potential cancer-fighting strategy .
Low levels of oxidative stress are thought to stimulate cell division in the promotion stage. Some scientists think that this might, along with many other complex factors, stimulate tumor growth. This hasn’t been proven in humans either, but .
these findings, though, an excess of antioxidants might theoretically increase the growth of existing tumors. This hasn’t been confirmed in large-enough studies, but some human findings are available.
In one study of breast cancer patients, antioxidant use during chemotherapy or radiation therapy was associated with worsened breast cancer prognosis in postmenopausal women .
A mice study published in 2019 even casts doubt on regularly using well-known antioxidants to improve health. The antioxidant N-acetylcysteine protected from COPD (lung emphysema) but induced lung cancer in mice .
It seems that tilting the balance in either direction – toward free radical excess or deficiency – may be detrimental.
It’s no surprise that antioxidant supplements aren’t a panacea – studies suggest that they are more ly to be harmful. But future research should clarify whether – and to what extent – antioxidant status and supplementation affect cancer risk.
Natural Antioxidant Defense
Living organisms have evolved a number of antioxidant defenses to maintain their survival against excessive oxidative stress .
To avoid free radical overproduction from oxidative stress, tissues naturally have antioxidants at their disposal. These antioxidants can neutralize free radicals .
Some common antioxidants include vitamins A, C, and E, glutathione, and the enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase .
Other antioxidants include lipoic acid, mixed carotenoids, coenzyme Q10, several bioflavonoids, antioxidant minerals (copper, zinc, manganese, and selenium), and various cofactors (folic acid, vitamins B1, B2, B6, B12) .
They work in synchrony when balanced. The body can produce some of them, while we can get the others in adequate amounts from a healthy diet .
The optimal source of antioxidants seems to come from our diet, not from antioxidant supplements, especially in well-nourished populations .
Vegetables and fruits are great sources of antioxidants. There is good evidence that eating a diet rich in vegetables and fruits is healthy .
Antioxidant supplements, on the other hand, have no known health benefits.
They have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.
According to the National Center for Complementary and Alternative Health :
“Rigorous scientific studies involving more than 100,000 people combined have tested whether antioxidant supplements can help prevent chronic diseases, such as cardiovascular diseases, cancer, and cataracts. In most instances, antioxidants did not reduce the risks of developing these diseases.”
Additionally, antioxidant supplements were not associated with a lower risk of dying in other studies [17, 18].
Concerns have been raised about associations between high doses of certain antioxidants and health risks. Beta-carotene supplementation has been linked with lung cancer in smokers, vitamin E with prostate cancer, and vitamin A with a higher risk of dying [17, 18].
Additionally, antioxidant supplements may interact with some medicines. Supplement-drug interactions can be dangerous and, in rare cases, even life-threatening.
Always consult your doctor before supplementing or making major changes to your diet and let them know about all drugs and supplements you are using or considering.
What Are Free Radicals?
The body is under constant attack from oxidative stress. Oxygen in the body splits into single atoms with unpaired electrons. Electrons to be in pairs, so these atoms, called free radicals, scavenge the body to seek out other electrons so they can become a pair. This causes damage to cells, proteins and DNA.
Free radicals are associated with human disease, including cancer, atherosclerosis, Alzheimer's disease, Parkinson's disease and many others. They also may have a link to aging, which has been defined as a gradual accumulation of free-radical damage, according to Christopher Wanjek, the Bad Medicine columnist for Live Science.
Substances that generate free radicals can be found in the food we eat, the medicines we take, the air we breathe and the water we drink, according to the Huntington's Outreach Project for Education at Stanford University. These substances include fried foods, alcohol, tobacco smoke, pesticides and air pollutants.
Free radicals are the natural byproducts of chemical processes, such as metabolism. Dr. Lauri Wright, a registered dietitian and an assistant professor of nutrition at the University of South Florida, said, “Basically, I think of free radicals as waste products from various chemical reactions in the cell that when built up, harm the cells of the body.”
Yet, free radicals are essential to life, Wanjek wrote in 2006. The body's ability to turn air and food into chemical energy depends on a chain reaction of free radicals. Free radicals are also a crucial part of the immune system, floating through the veins and attacking foreign invaders.
The danger of free radicals
According to Rice University, once free radicals are formed, a chain reaction can occur.
The first free radical pulls an electron from a molecule, which destabilizes the molecule and turns it into a free radical.
That molecule then takes an electron from another molecule, destabilizing it and tuning it into a free radical. This domino effect can eventually disrupt and damage the whole cell.
The free radical chain reaction may lead to broken cell membranes, which can alter what enters and exits the cell, according to the Harvard School of Public Health. The chain reaction may change the structure of a lipid, making it more ly to become trapped in an artery. The damaged molecules may mutate and grow tumors. Or, the cascading damage may change DNA code.
Oxidative stress occurs when there are too many free radicals and too much cellular damage. Oxidative stress is associated with damage of proteins, lipids and nucleic acids, according to an article in the Pharmacognosy Review.
Several studies throughout the last few decades have suggested that oxidative stress plays a role in the development of many conditions, including macular degeneration, cardiovascular disease, certain cancers, emphysema, alcoholism, Alzheimer's disease, Parkinson's disease, ulcers and all inflammatory diseases, such as arthritis and lupus.
Free radicals are also associated with aging. “The free radical theory of aging states that we age because of free radical damage over time,” said Wright. Free radicals can damage DNA's instructional code, causing our new cells to grow incorrectly, leading to aging.
Symptoms of oxidative stress
According to a 2010 article in Methods of Molecular Biology, there are no officially recognized symptoms of oxidative stress. According to naturopathic doctor Donielle Wilson’s website, however, symptoms include fatigue, headaches, noise sensitivity, memory loss and brain fog, muscle and joint pain, wrinkles and gray hair, vision trouble and decreased immunity.
Testing for free radicals
It is not possible to directly measure the amount of free radicals in the body, according to Rice University.
According to a 2000 article in theAmerican Journal of Clinical Nutrition, there are indirect methods of measuring oxidative stress, usually involving analysis of the byproducts of lipid peroxidation.
The article warns that all methods should “should be used with caution because of the lack of accuracy, validity or both.”
The more recent article in Methods of Molecular Biology states that kits for testing oxidative stress are increasingly available, though their accuracy and validity are still under scrutiny.
Antioxidants and free radicals
Antioxidants keep free radicals in check. Antioxidants are molecules in cells that prevent free radicals from taking electrons and causing damage. Antioxidants are able to give an electron to a free radical without becoming destabilized themselves, thus stopping the free radical chain reaction.
“Antioxidants are natural substances whose job is to clean up free radicals. Just fiber cleans up waste products in the intestines, antioxidants clean up the free radical waste in the cells,” said Wright.
Well-known antioxidants include beta-carotene and other carotenoids, lutein, resveratrol, vitamin C, vitamin E, lycopene and other phytonutrients.
Our body produces some antioxidants on its own, but an insufficient amount. Oxidative stress occurs when there is an imbalance of free radicals and antioxidants (too many free radicals and too few antioxidants), according to the Pharmacognosy Review.
Antioxidants can be acquired through diet. “Antioxidants are plentiful in fruits and vegetables, especially colorful fruits and vegetables,” said Wright. “Some examples include berries, tomatoes, broccoli, spinach, nuts and green tea.”
Antioxidants became well known in the 1990s when scientists began to realize the possible effects of free radicals on cancer development, atherosclerosis and other chronic conditions.
During the subsequent decades, scientists have conducted many studies on the effects of antioxidants with mixed results. Wright gave a few examples.
“A six-year trial, the Age-Related Eye Disease Study (AREDS), found that a combination of vitamin C, vitamin E, beta-carotene and zinc offered some protection against the development of advanced age-related macular degeneration,” she said.
On the other hand, Wright mentioned that a beta-carotene trial among Finnish men who were heavy smokers found an increase in lung cancer among those taking beta-carotene supplements.
Scientists do not completely understand the mixed results from the trials or the exact mechanism that makes antioxidants effective or ineffective against free radicals, but according to Wright, the study results suggest that it is more effective and potentially safer to get antioxidants through whole foods rather than supplements.
Free radicals and exercise
According to an article in Biochemical Society Transactions, intense aerobic exercise can induce oxidative stress. Burning fuel in high-intensity cardio exercise causes chemical reactions that make free radicals form at a faster rate.
This isn't an excuse to skip the gym, however. According to an article in the American Journal of Clinical Nutrition, frequent exercise training seems to reduce the oxidative stress initially brought on by exercise.
This is because regular physical exercise enhances antioxidant defenses.
Spurred by the concern that intense exercise could cause oxidative stress, several studies were conducted to look at the effects of antioxidant supplementation for athletes.
The American Journal of Clinical Nutrition article said that supplementing high intensity exercise with antioxidant supplements produced no beneficial effects, however.
Regular exercise alone was enough to build up antioxidant defenses against the initial exercise-induced oxidative stress.
Therefore, shape and infrequent exercisers who do a spontaneous b intense physical activity may invoke oxidative stress, while those who are consistently active should not worry.
Natural Remedies for Fighting Oxidative Stress
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