Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the body’s ability to counteract or detoxify their harmful effects through antioxidant mechanisms. This phenomenon plays a crucial role in various physiological processes and has been implicated in the development and progression of numerous health conditions, including cardiovascular diseases, neurodegenerative disorders, and cancer. In this comprehensive blog post, we will delve into the intricacies of oxidative stress, shedding light on its underlying mechanisms, associated health implications, and strategies to mitigate its impact.
Welcome to my blog Oxidative Stress: What You Need To Know.
Understanding Oxidative Stress: The Silent Culprit Behind Many Health Issues
In the realm of functional medicine, we often encounter the term “oxidative stress.” But what exactly does it mean, and why should we pay attention to it? Let’s delve into this crucial concept that plays a significant role in our overall health and well-being.
What is Oxidative Stress?
At its core, oxidative stress refers to an imbalance between free radicals and antioxidants in the body. To grasp this, let’s break it down a bit further.
Free Radicals: These are highly reactive molecules that contain unpaired electrons. They are produced naturally in the body during metabolic processes, but they can also be generated by external factors like pollution, cigarette smoke, and UV radiation.
Antioxidants: On the other hand, antioxidants are molecules that neutralise free radicals by donating one of their own electrons. They act as our body’s defence mechanism against the harmful effects of oxidative stress.
Under normal circumstances, our body can manage the production of free radicals and neutralise them effectively with antioxidants. However, when the balance is disrupted, and there’s an excess of free radicals or a deficiency of antioxidants, oxidative stress occurs.
Pro-oxidant–Antioxidant Balance
The concept of a pro-oxidant–antioxidant balance is central to an understanding of oxidative stress for several reasons. Firstly, it emphasises that the disturbance may be caused through changes on either side of the equilibrium (e.g. abnormally high generation of ROS or deficiencies in the antioxidant defences).
Secondly, it highlights the homeostatic concentrations of ROS. Although ROS first came to the attention of biologists as potentially harmful by-products of aerobic metabolism, it is now recognised that they play important roles as secondary messengers in many intracellular signalling pathways. Finally, the concept of a balance draws attention to the fact that there will be a graded response to oxidative stress. Hence, minor disturbances in the balance are likely to lead to homeostatic adaptations in response to changes in the immediate environment, whereas more major perturbations may lead to irreparable damage and cell death.
The boundary between normal physiological changes and pathological insults is therefore inevitably indistinct. (source)
It Never Happens In Isolation
A further feature of oxidative stress that affects its clinical presentation is that it rarely occurs in isolation. It is now appreciated that complex interactions take place between oxidative and other forms of cell stress, such as endoplasmic reticulum (ER) stress.
The clinical manifestation will therefore depend on the balance of metabolic activities in a particular cell type or organ, and so may vary from system to system. (source)
Where Do Reactive Oxygen Species Come From?
Here are some primary sources of ROS in the body:
Mitochondria
Mitochondria are the powerhouse of the cell where energy production occurs through oxidative phosphorylation. During this process, a small percentage of oxygen molecules may undergo incomplete reduction, resulting in the generation of ROS, particularly superoxide radicals (O2•−). Mitochondrial ROS production can increase under conditions of high energy demand or mitochondrial dysfunction.
NADPH oxidases (NOX enzymes)
NADPH oxidases are a family of enzymes primarily responsible for generating ROS as part of the immune response. They produce superoxide radicals by transferring electrons from NADPH to molecular oxygen. NOX enzymes are found in various cell types, including immune cells like neutrophils and macrophages, where they play crucial roles in host defense against pathogens.
Xanthine oxidase
Xanthine oxidase is an enzyme involved in purine metabolism, catalyzing the conversion of hypoxanthine to xanthine and then to uric acid. During this process, xanthine oxidase generates ROS, particularly superoxide radicals and hydrogen peroxide. Increased xanthine oxidase activity is associated with conditions such as inflammation, ischemia-reperfusion injury, and oxidative stress-related diseases.
Cytochrome P450 enzymes
Cytochrome P450 enzymes are a family of heme-containing proteins involved in the metabolism of endogenous and exogenous compounds, including drugs and toxins. Some cytochrome P450 isoforms can produce ROS as byproducts of their enzymatic reactions, particularly during the metabolism of certain xenobiotics and drugs.
Inflammation and immune activation
Inflammatory cells such as neutrophils and macrophages produce ROS as part of the respiratory burst, a rapid release of ROS aimed at destroying pathogens. ROS generated by activated immune cells help eliminate invading microorganisms but can also cause collateral damage to surrounding tissues if not properly regulated.
Ultraviolet (UV) radiation
Exposure to UV radiation from sunlight can induce ROS production in the skin through various mechanisms, including direct excitation of oxygen molecules and activation of cellular pathways leading to ROS generation. UV-induced ROS contribute to skin aging, inflammation, and DNA damage, increasing the risk of skin cancer.
Understanding the sources of ROS is crucial for comprehending the role of oxidative stress in health and disease. While ROS are necessary for physiological functions, maintaining a balance between ROS production and antioxidant defenses is essential for preventing oxidative damage and maintaining cellular homeostasis. (source)
What Causes Oxidative Stress?
They are normally generated as by-products of oxygen metabolism; despite this, environmental stressors (i.e., UV, ionizing radiations, pollutants, and heavy metals) and xenobiotics contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress). (source)
What Conditions Are Associated With Oxidative Stress?
A large body of evidences shows that oxidative stress can be responsible, with different degrees of importance, in the onset and/or progression of several diseases (i.e., cancer, diabetes, metabolic disorders, atherosclerosis, and cardiovascular diseases) (source)
Cancer
Cancer starts in the body through a series of changes in cells and molecules, triggered by both internal and external factors. Oxidative damage to DNA, caused by things like smoking, pollution, and inflammation, is a known trigger for cancer development. This damage can lead to abnormalities in chromosomes and the activation of cancer-causing genes due to stress. When DNA is damaged, it can disrupt normal cell growth and cause mutations in genes. Oxidative stress can also cause various other changes in DNA, such as breaks and alterations in its structure. Lifestyle factors, like diet high in fats, can contribute to cancer risk by increasing oxidative stress in the body.
Cardiovascular Disease and Oxidative Stress
Cardiovascular diseases (CVDs) are health conditions involving the heart and blood vessels, caused by various factors. Some well-known factors include high cholesterol, high blood pressure, smoking, diabetes, unhealthy diet, stress, and lack of physical activity. Recent research suggests that oxidative stress plays a significant role in the development of many CVDs. Oxidative stress primarily triggers a process called atherosclerosis, where plaque builds up in the arteries.
This plaque starts with inflammation in the artery lining, which attracts certain immune cells that produce reactive oxygen species. These harmful molecules then oxidize LDL cholesterol, leading to the formation of fatty deposits called foam cells and eventually the development of atherosclerotic plaques. Both laboratory and animal studies have provided evidence supporting the role of oxidative stress in various cardiovascular conditions like atherosclerosis, heart attacks, high blood pressure, heart muscle diseases, and heart failure.
Neurological Disease and Oxidative Stress
Oxidative stress has been linked to several neurological diseases (i.e., Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss). In AD, several experimental and clinical researches showed that oxidative damage plays a pivotal role in neuron loss and progression to dementia. β-amyloid, a toxic peptide often found present in AD patients’ brain, is produced by free radical action and it is known to be at least in part responsible for neurodegeneration observed during AD onset and progression.
Respiratory Disease and Oxidative Stress
Several researches pointed out that lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), determined by systemic and local chronic inflammation, are linked to oxidative stress. Oxidants are known to enhance inflammation via the activation of different kinases involving pathways and transcription factors like NF-kappa B and AP-1.
Rheumatoid Arthritis and Oxidative Stress
Rheumatoid arthritis is a chronic inflammatory disorder affecting the joints and surrounding tissues, characterised by macrophages and activated T cell infiltration. Free radicals at the site of inflammation play a relevant role in both initiation and progression of this syndrome, as demonstrated by the increased isoprostane and prostaglandin levels in synovial fluid of affected patients.
Kidney Diseases and Oxidative Stress
Oxidative stress, which occurs when there’s an imbalance between antioxidants and harmful molecules called reactive oxygen species (ROS), plays a significant role in numerous kidney diseases. These include inflammation of the kidney’s filtering units (glomerulonephritis), inflammation of the kidney tissue (tubulointerstitial nephritis), kidney failure, abnormal amounts of protein in the urine (proteinuria), and the buildup of waste products in the blood (uremia).
Oxidative stress harms the kidneys primarily by triggering inflammation. When ROS levels rise, they prompt the recruitment of inflammatory cells and the production of molecules that promote inflammation, such as TNF-alpha and IL-1b. These molecules, along with a transcription factor called NF-κB, initiate an inflammatory response. As inflammation progresses, another molecule called TGF-beta becomes more prevalent, leading to the synthesis of excess connective tissue in the kidney (fibrosis).
Chronic exposure to oxidative stress can result in an ongoing cycle of inflammation and fibrosis in the kidneys, ultimately leading to kidney failure. Certain medications like cyclosporine, tacrolimus, gentamycin, and bleomycin can exacerbate oxidative stress in the kidneys, further damaging them. Additionally, exposure to heavy metals like cadmium, mercury, lead, and arsenic, as well as transition metals like iron, copper, cobalt, and chromium, can also induce oxidative stress and contribute to kidney diseases and some types of cancer.
How To Test For Oxidative Stress
There are several laboratory tests available for this purpose. Here are some common ones:
Oxidative Stress Biomarkers
These tests measure specific biomarkers that indicate oxidative stress levels in the body. Some commonly measured biomarkers include:
- Malondialdehyde (MDA): A marker of lipid peroxidation.
- 8-Hydroxy-2′-deoxyguanosine (8-OHdG): Reflects oxidative damage to DNA.
- Isoprostanes: These are prostaglandin-like compounds formed from the free radical-catalysed peroxidation of arachidonic acid. They are often measured in urine or plasma.
Total Antioxidant Capacity (TAC)
This test measures the overall ability of the body to counteract oxidative stress by neutralising free radicals. It provides an indication of the body’s antioxidant defence system.
Glutathione Levels
Glutathione is a powerful antioxidant produced by the body. Assessing levels of reduced (GSH) and oxidised (GSSG) glutathione can provide insights into the body’s antioxidant capacity.
Reactive Oxygen Species (ROS) Assay
This test measures the levels of reactive oxygen species directly in the blood or tissues.
Advanced Oxidation Protein Products (AOPP)
These are markers of protein oxidation and can be measured in plasma.
F2-Isoprostanes
These are prostaglandin-like compounds formed from the free radical-catalysed peroxidation of arachidonic acid. They are often measured in urine or plasma.
C-reactive Protein (CRP)
While primarily a marker of inflammation, elevated levels of CRP may indirectly indicate increased oxidative stress.
It’s important to note that while these tests can provide valuable insights into oxidative stress levels, they should be interpreted alongside a comprehensive assessment of your health status, including medical history, symptoms, and other laboratory tests. Additionally, individual variations and factors such as age, sex, and lifestyle habits should be taken into account when interpreting results.
How To Reduce Oxidative Stress
The human body has two primary ways of managing oxidative stress:
- Enogenous antioxidant systems (stimulated by various factors ranging from exposure to a compound through to exercise)
- Exogenous antioxidants (from food or supplements)
Endogenous antioxidants can be further subdivided in to enzymatic (e.g., SOD, CAT, and GPx) and nonenzymatic (e.g., lipoic acid, glutathione, ʟ-arginine, and coenzyme Q10) antioxidant molecules. (source).
Dietary Strategies
A nutrient-rich diet forms the cornerstone of any strategy to combat oxidative stress. Key dietary principles include:
- Antioxidant-Rich Foods: Incorporate a variety of fruits, vegetables, nuts, seeds, and whole grains into your diet. These foods are rich in vitamins (such as vitamin C and E), minerals (like selenium and zinc), and phytonutrients (such as flavonoids and carotenoids) that act as antioxidants, scavenging free radicals and protecting cells from damage.
- Omega-3 Fatty Acids: Increase consumption of omega-3 fatty acids found in fatty fish (such as salmon, mackerel, and sardines), flaxseeds, chia seeds, and walnuts. Omega-3s possess anti-inflammatory properties, helping to counteract the inflammatory effects associated with oxidative stress.
- Limit Processed Foods and Sugars: Reduce intake of processed foods, refined sugars, and unhealthy fats, which can promote inflammation and oxidative damage. Opt for whole, minimally processed foods whenever possible.
- Stay Hydrated: Drink plenty of water throughout the day to support detoxification processes and maintain cellular hydration, which is essential for optimal cellular function.
Physical Activity
Regular exercise is another powerful tool for combating oxidative stress. Exercise increases the body’s antioxidant defenses while promoting detoxification through sweat and improved circulation. Aim for a combination of cardiovascular exercise, strength training, and flexibility exercises to reap the full benefits of physical activity.
Stress Management
Chronic stress is a significant contributor to oxidative stress and inflammation. Incorporate stress-reduction techniques such as mindfulness meditation, deep breathing exercises, yoga, tai chi, or spending time in nature to promote relaxation and balance the body’s stress response.
Quality Sleep
Prioritise adequate sleep to support cellular repair and regeneration. Aim for 7-9 hours of quality sleep each night, and establish a consistent sleep schedule to optimise circadian rhythms and hormone production.
Avoid Harmful Substances
Limit exposure to environmental toxins, pollutants, and harmful substances such as tobacco smoke and excessive alcohol. These substances can overwhelm the body’s antioxidant defences and contribute to oxidative damage.
Supplementation
In some cases, supplementation with targeted antioxidants or other nutritional supplements may be beneficial, particularly for individuals with specific health concerns or deficiencies. However, supplementation should be personalized and guided by a healthcare professional to ensure safety and efficacy.
Here, we will discuss the most relevant nutritional antioxidants and their protective effects for human health.
Vitamin E
The term vitamin E encompasses a constellation of lipophilic molecules (α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol).
Vitamin E modulates the oxidative stress-induced NF-κB pathway and oxLDL-induced foam cell formation, decreases c-Jun phosphorylation (thus inhibiting inflammation and monocyte invasion).
Flavonoids
Flavonoids are a class of polyphenolic compounds with a benzo-γ-pyrone structure largely represented in plants, responsible for several pharmacological activities. These substances have been investigated because of their potential health benefits as antioxidants, action mediated by their functional hydroxyl groups, which are able to scavenge free radicals and/or chelate metal ions.
Their antioxidant activity relies on the conformational disposition of functional groups; configuration, substitution, and total number of hydroxyl groups are important factors in determining mechanisms of antioxidant activity like ROS/RNS scavenging and metal chelation.
Flavonoid determines (i) ROS synthesis suppression, inhibition of enzymes, or chelation of trace elements responsible for free radical generation; (ii) scavenging ROS; and (iii) improvement of antioxidant defenses.
Genistein
Genistein is a soy isoflavone that is probably the most interesting and well-studied flavonoid compound, due to its broad pharmacological activities.
Genistein has been extensively employed as antioxidant in a plethora of studies, showing the potential to scavenge ROS and RNS with a high degree of efficacy. This flavonoid compound is able to improve the antioxidant defenses of a cell, thus prevents apoptotic process through the modulation of several genes and proteins. In nonhuman primates and rabbits, dietary-supplemented genistein delayed atherogenesis. An additional study observed an increase in antioxidant protection of LDL and an atheroprotective effect. In general, soy isoflavones confer protection against lipoprotein oxidation, as well as against oxidative DNA damage in postmenopausal women, but the point is still debated.
There are other mechanism that genistein can be used to suppress oxidative stress and related inflammation in the vascular intima layer. Genistein inhibits NF-κB activation (inducible by oxidative stress) and regulates the expression of genes relevant to immune and inflammatory processes. Genistein increases the expression of antioxidant enzymes in human prostate cancer cells conferring protection against oxidative DNA damage.
Glutathione
Glutathione is the major cellular redox buffer in cells, and is made from the amino acids l-glutamate, l-cysteine and glycine. Glutathione participates in a large number of detoxifying reactions. (source)
Alpha-Lipoic acid
Alpha-Lipoic Acid scavenges reactive ROS, and regenerates vitamins C and E, and glutathione in their active forms. Lipoic acid also has a role in metal chelation – but it is a weak chelator in this regard.
Melatonin
Melatonin is a neurohormone derived from amino acid tryptophan. It is involved in circadian rhythms but also acts as a potent antioxidant, protecting cell membranes against lipid peroxidation. (source)
CoQ10
Coenzyme Q10 or ubiquinone is an antioxidant present in cell membranes. It is one of the few liposoluble antioxidants, ensuring lipoproteins and lipids protection from radical chain reactions, peroxidation and oxidative damage. In its active form (quinol), coenzyme Q10 can scavenge several reactive oxygen species or regenerate other oxidized antioxidants (including vitamins C and E). (source)
Polyphenols
Several biological functions have been ascribed to polyphenols, including anti-inflammatory, antioxidant, antimicrobial and antimelanogenesis effects, suggesting their use in the human diet and as food supplements. The most widely recognized polyphenols’ classes are flavonoids, phenolic acids, stilbenes (including resveratrol), tannins, coumarins, curcuminoids and lignans. For instance, one of the most studied polyphenols has been curcumin, gaining a lot of attention also for nutraceutical applications. This phytochemical has, in fact, potent activity as a scavenger for superoxide anions, lipid peroxides, and several reactive nitrogen species. Curcumin can also increase glutathione cellular levels.
Garlic
Organosulfur compounds have also been suggested as potent antioxidants. The most studied are probably some sulfur-containing metabolites present in garlic (mainly S-allyl-mercapto cysteine, S-allyl cysteine, and diallyl sulfide, diallyl trisulfide). These organosulfur are also responsible for typical garlic flavor. Their antioxidant actions include scavenging ROS and inhibiting lipids peroxidation.
Minerals
Selenium is a necessary component of GPX, while copper, zinc, and manganese are fundamental for SOD activity
Can Oxidative Stress Be Reversed?
Oxidative stress is a normal, natural, process. In this question we are implying someone has chronically elevated levels. And on this basis, the answer is yes it can. But it depends on understanding the mechanisms causing it in your unique situation. The underlying imbalances must be resolved to successfully reverse oxidative stress. It is not as simple as adding in the above foods or supplements.
