Reactive Oxygen Species (ROS) are vital for cell signaling but harmful in excess, causing oxidative stress that damages cells and contributes to aging and diseases. Maintaining balance through antioxidants and healthy lifestyle choices is key to protecting cellular health and preventing chronic conditions.
Introduction
Each and every living cell is constantly striving for a state of balance. This intrinsic ability to maintain a stable internal state, crucial for life and function, is referred to as homeostasis1. But why and how do our cells maintain this harmony?
By regulating their internal environment, cells can maintain stable conditions despite external fluctuations, allowing room for proper enzyme activity and other cellular processes. They do so by regulating transport of ions and small molecules and communicating with neighboring cells.
Within the constraints of this delicate balance, molecules that at first might seem like adversaries, play vital roles. Among these molecules are Reactive Oxygen Species (ROS)—naturally occurring molecules that play roles in essential cellular signaling and physiological processes, and high levels of which can lead to oxidative damage2, 3.
However, when production of these ROS overwhelms the defense mechanisms of the cell, oxidative stress ensues, contributing significantly to a plethora of diseases4. This nuanced interplay thus represents a fine line that can be key to unlocking new avenues for treatment.
Reactive oxygen species (ROS)
What exactly are ROS?
ROS are, essentially, a class of highly reactive, oxygen-derived molecules, many of which are free radicals. This makes them highly unstable and eager to react with other molecules for achieving stability5. Non-radical ROS are also highly reactive due to their specific chemical configurations6.
The most common players in the ROS family include the primary ROS—superoxide radical (O2⋅−), and hydroxyl radical (⋅OH), the most potent and damaging of all. Non-radical examples include hydrogen peroxide (H2O2), a relatively stable signaling molecule, and singlet oxygen (1O2), a highly excited form of oxygen.
Where do ROS come from?
ROS are generated all around our biological systems, both from within our bodies and from the environment that surrounds us.
The most significant internal source is the mitochondria7. As they generate energy in the form of ATP through the electron transport chain, a small fraction of electrons leaks and react with oxygen, forming the highly potent superoxide radicals8. This occurs as we breathe and metabolize food. Enzyme classes, such as NADPH oxidases (NOXs) employ immune cells to generate superoxide, resulting in the “oxidative burst”, to kill invading pathogens9. Xanthine oxidase and lipoxygenases are some other enzymes that contribute, along with other organelles including peroxisomes and the endoplasmic reticulum, as part of their normal operations10-13.
In course of our daily life, we are constantly exposed to external sources that can significantly increase ROS levels.
- Breathing polluted air containing ozone and particulate matter, exposure to industrial chemicals and heavy metals such as lead, cadmium, and arsenic can lead to the formation of ROS14, 15.
- Radiation exposure, whether from the sun’s UV radiation, or from X-rays and radiotherapy, can split water molecules, activating cellular pathways to produce ROS in large quantities16. Smoking and alcohol consumption also pose as major contributors, prompting ROS-generating pathways17.
- Furthermore, chronic inflammation and infection cause sustained activation of immune cells and are significant sources of ROS18.
The “Good” side of ROS
Despite their general reputation of being damaging, ROS are not inherently harmful. At low to moderate concentrations, they activate specific cascades that influence gene expression, cell proliferation, differentiation, and apoptosis, functioning as intracellular messengers19-21.
Their duality gets most pronounced in the way they induce immune responses. Immune cells such as phagocytes generate huge quantities of superoxide and hydrogen peroxide through an “oxidative burst” to kill invading microorganisms in a targeted manner9. Thus, by regulating various physiological processes, ROS help in maintaining cellular homeostasis.
Oxidative stress
While ROS are naturally occurring and even beneficial in moderate levels, it’s their imbalance that triggers oxidative stress, pushing the system from beneficial to destructive.
Defining the imbalance
Oxidative stress occurs when the generation of ROS in a biological system surpasses the neutralizing capacity of the antioxidant defense mechanisms. This disrupts the normal redox homeostasis, leading to cellular damage.
How excess ROS harms cells and tissues
Excessive ROS levels attack fundamental cellular components, causing widespread damage:
- Lipid peroxidation: The hydroxyl radical form of ROS attacks the polyunsaturated fatty acids of cell membranes, damaging their structural integrity by a process known as lipid peroxidation22. This causes loss of fluidity, enhanced permeability, and eventually, cell lysis. It also leads to generation of highly toxic byproducts such as malondialdehyde and 4-hydroxynonenal, which can end up harming other cellular components22.
- Protein oxidation: These free radicals can modify amino acids, changing protein structure, leading to the loss of enzyme activity, and formation of faulty protein aggregates. Protein oxidation impairs everything from metabolism and transport to signaling and structural support23.
- DNA and RNA damage: ROS can oxidize nucleotide bases of DNA and RNA, forming 8-oxoguanine, causing strand breaks and inducing cross-linking24. Such damage can lead to mutations, impaired DNA replication and repair mechanisms, and ultimately, genomic instability—a hallmark of aging and cancer.
- Carbohydrate damage: Although less extensively studied than damage to lipids, proteins, and DNA, ROS can also attack and modify carbohydrates, affecting their structure and function within the cell25.
However, the tipping point towards oxidative stress is more than just about increased ROS production. A lowered antioxidant defense and persistent inflammation can leave the body vulnerable to even normal ROS levels.
Antioxidant defense systems
Fortunately, our bodies come with sophisticated defense mechanisms specifically designed to counteract ROS and prevent oxidative stress. These are the antioxidants, molecules that can neutralize ROS, scavenge free radicals, or inhibit their formation, thereby protecting cells from damage4. They are crucial for maintaining redox balance and ensuring cellular integrity.
Internal antioxidant systems
Our cells naturally produce a formidable array of antioxidants. These include enzymatic antioxidants, which efficiently catalyze proteins, converting harmful ROS into less damaging molecules. Key players include
- Superoxide dismutase, which converts superoxide into hydrogen peroxide26.
- Catalase, which breaks down hydrogen peroxide into harmless water and oxygen27.
- Glutathione peroxidase, which uses glutathione to reduce hydrogen peroxide and organic hydroperoxides28.
Other than enzymes, our body also relies on non-enzymatic antioxidants—smaller molecules that directly scavenge free radicals. Glutathione, the “master antioxidant,” is abundant in cells and plays a versatile role in direct radical scavenging and detoxification29. Other important endogenous scavengers include uric acid, bilirubin, and alpha-lipoic acid30-32.
Dietary antioxidants
Some essential antioxidants including crucial vitamins like Vitamins C and E are obtained through our diet. Carotenoids such as beta-carotene and lycopene, found in colorful fruits and vegetables, serve as potent lipid-soluble antioxidants that are effective at quenching singlet oxygen33. A vast group of plant compounds called polyphenols exhibit diverse antioxidant mechanisms34.
Additionally, trace minerals such as selenium, zinc, copper, and manganese are essential cofactors for the proper functioning and activity of the body’s key enzymatic antioxidant systems, but they are not antioxidants themselves35.
Oxidative stress and disease
The collective damage inflicted by persistent oxidative stress contributes significantly to the development and progression of numerous chronic diseases, as well as the very process of aging.
According to one of the leading theories of aging, cellular senescence is mainly driven by the lifelong accumulation of oxidative damage to macromolecules, tissue dysfunction, and the overall decline associated with aging36.
In neurodegenerative diseases, for instance, the high oxygen consumption and specific lipid composition of the brain make neurons particularly vulnerable to oxidative damage37. Oxidative stress has been found to contribute significantly to neuronal dysfunction and death, leading to conditions such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis.
Oxidative stress also plays a critical role in cardiovascular diseases38. It contributes to endothelial dysfunction, promotes the oxidation of Low Density Lipoprotein (bad cholesterol), and fuels inflammation, all of which are key steps in the development of atherosclerotic plagues and hypertension.
ROS-induced DNA damage is also a direct cause of mutations, which can initiate carcinogenesis39. Furthermore, ROS can alter cell signaling pathways, promoting uncontrolled cell proliferation, inhibiting apoptosis, and driving tumor development and progression. Oxidative stress has significant roles in both the initiation and growth of many forms of cancers.
Oxidative stress is a major player for metabolic disorders such as diabetes and obesity40. It contributes to insulin resistance, impairs the function of insulin-producing pancreatic beta cells, and drives the development of various complications affecting the eyes, kidneys, and nerves.
Chronic inflammatory diseases like rheumatoid arthritis and inflammatory bowel disease are characterized by persistent immune cell activation, leading to excessive ROS production41, 42. This, in turn, exacerbates inflammatory response and tissue damage.
Oxidative stress leads to many other health challenges, including autoimmune diseases, chronic kidney disease, various respiratory diseases, and common eye conditions like cataracts and age-related macular degeneration43-46.
Managing oxidative stress
Given the extensive role of oxidative stress in health and disease, strategies aimed at maintaining redox balance are crucial.
Lifestyle interventions
Empowering individuals to make informed lifestyle choices is fundamental:
- A balanced diet rich in fruits, vegetables, whole grains, nuts, and seeds is the most effective way to support antioxidant defenses47. These foods provide a complex array of natural antioxidants, vitamins, and minerals that work synergistically to manage ROS levels.
- Regular physical activity at a moderate level can enhance the body’s antioxidant enzyme systems. This improves its ability to handle ROS47.
- Stress management techniques like meditation and adequate sleep can help mitigate the link between increased oxidative stress and psychological stress48.
- Avoiding environmental toxins such as cigarette smoke, excessive alcohol consumption, and minimizing exposure to air pollution can also contribute to lowering oxidative burden17.
Antioxidant supplementation: cautions and considerations
Research on isolated antioxidant supplements has yielded mixed results, and in some cases, high doses have shown no benefit, even causing potential harm, as seen in increased cancer risk in smokers taking beta-carotene49. The intricate redox signaling system of our body depends on precise ROS levels, and overwhelming the system with external antioxidants can sometimes disrupt this delicate balance. The benefits of antioxidants are best obtained from a diverse diet rich in whole foods, where these compounds work in concert with other beneficial nutrients.
Therapeutic approaches
Scientific advancements are paving way for more targeted interventions, into pharmaceutical compounds or specific nutritional components. These can modulate antioxidant enzyme activity, effectively boosting the body’s intrinsic defense systems.
Scientists are working on targeting specific ROS-producing pathways, to develop drugs that inhibit excessive ROS generation from particular sources without disrupting ROS signaling that are actually beneficial50.
The future may also involve personalized nutrition and medicine, where antioxidant strategies are tailored based on an individual’s genetic predisposition and specific oxidative stress biomarkers, leading to more precise and effective interventions51, 52.
Conclusion
In the grand scheme of cellular life, reactive oxygen species represent a double-edged sword. They are indispensable for vital cellular functions, acting as messengers in important physiological processes. Yet, when their production spirals out of control, the resulting oxidative stress becomes a potent force for cellular damage, contributing to aging and a vast array of chronic diseases.
The goal, therefore, is to maintain the crucial redox homeostasis: a delicate balance between ROS generation and antioxidant defense, without trying to eliminate all ROS53. By embracing lifestyle choices that support our natural defenses, and by understanding the intricate mechanisms involving ROS, we can navigate the complexities of cellular health.