A Fine Balance
30th of March 2024
•Should Concerned Individuals Resort to Antioxidant Supplements Amid 5G Fears?
•Examining the Wisdom of Taking Antioxidants for EMF and Cell Tower Worries
Oxidative stress; ROS
Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify or repair the resulting damage. The chemical oxidation and reduction reactions are the basis for all biochemical processes that make biological activities and life possible. The relatively reactive molecular oxygen in our atmosphere plays a key role in generating energy from sunlight and in the conversion of this energy through cellular respiration in the mitochondria to make it available for other biological processes. For the functionality of cells and the organism, it is therefore essential that the reducing and oxidising molecules are in balance. This is known as redox equilibrium, which is controlled and maintained by the cell’s own sensors, signalling pathways and defence mechanisms. If imbalanced in direction of an increase in oxidative processes, we speak of oxidative stress.*
Reactive oxygen species (ROS) are formed as natural byproducts of cellular metabolism.
The importance of reactive oxygen species (ROS) has been gradually acknowledged over the last four decades. Initially perceived as unwanted products of detrimental oxidative stress, they have been upgraded since, and now ROS are also known to be essential for the regulation of physiological cellular functions through redox signaling. (Milkovic et al., 2019).
The formation of ROS plays a fundamental role in many processes of neuronal development, plasticity and signal transduction to ensure normal functionality. (Oswald, M.C.W., et al., 2018)
An increase in ROS formation does not inevitably result in health-related and negative effects
We are not without protection against ROS!
Our bodies and plant cells have many different enzymes and antioxidants that are used to scavenge or detoxify reactive oxygen species
There is a constant production of ROS in our bodies but at the same time a constant process of ROS scavenging or detoxification.
The Difference between Eustress and Distress
Eustress is physiological oxidative stress that is necessary for cellular processes.
Distress is harmful oxidative stress
There is no clearly defined boundary between Eustress and Distress.
Redox homeostasis
ROS production is not inherently harmful but rather finely regulated to maintain cellular homeostasis and functionality.
We cannot only regard reactive oxygen species as a toxic by-product of mitochondrial respiration.
Previously thought of as harmful agents only, they are now considered as important signaling molecules with potential therapeutic effect. Ref: Holzerová E, Prokisch H. Mitochondria: Much ado about nothing? How dangerous is reactive oxygen species production? Int J Biochem Cell Biol. 2015 Jun;63:16-20. doi: 10.1016/j.biocel.2015.01.021. Epub 2015 Feb 7. PMID: 25666559; PMCID: PMC4444525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444525/
ROS Function in Redox Signaling and Oxidative Stress
Studies over the past two decades in various organisms, tissues and cell types have led to a shift in our understanding of ROS: we no longer view them just as molecules that invoke damage (i.e. oxidative stress) but now also appreciate their role in regulating signaling pathways that impinge on normal physiological and biological responses (i.e. redox biology). Ref. Michael Schieber, Navdeep S. Chandel, ROS Function in Redox Signaling and Oxidative Stress, Current Biology, Volume 24, Issue 10, 2014, Pages -R462, ISSN 0960-9822, https://doi.org/10.1016/j.cub.2014.03.034.(https://www.sciencedirect.com/science/article/pii/S0960982214003261)
Oxidative Stress: Harms and Benefits for Human Health
In this review, from 2017, the authors described the findings in the oxidative stress field, highlighting both its bad and good sides for human health. Ref. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 2017;2017:8416763. doi: 10.1155/2017/8416763. Epub 2017 Jul 27. PMID: 28819546; PMCID: PMC5551541 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551541/
Editorial: The Role of Reactive Oxygen Species in Protective Immunity
ROS are not only essential for antimicrobial defense but also exert a variety of crucial regulatory functions, reaching from the modulation of transcriptional programs to mediating differentiation fate. On the other hand, oxidative stress can contribute to various pathologies, including neuronal degenerative diseases, autoimmunity as well as cancer. Therefore, the potential therapeutic intervention in ROS biology will need extensive temporal and spatial fine tuning. Ref. Martinvalet D and Walch M (2022) Editorial: The Role of Reactive Oxygen Species in Protective Immunity. Front. Immunol. 12:832946. doi: 10.3389/fimmu.2021.832946 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.832946/full
The Two Faces of Reactive Oxygen Species in Cancer
The role of ROS in cancer is not one-sided.
Reactive oxygen species (ROS), now appreciated for their cellular signaling capabilities, have a dual role in cancer. On the one hand, ROS can promote protumorigenic signaling, facilitating cancer cell proliferation, survival, and adaptation to hypoxia. On the other hand, ROS can promote antitumorigenic signaling and trigger oxidative stress–induced cancer cell death. Ref. Reczek, C. R., & Chandel, N. S. (2017). The two faces of reactive oxygen species in cancer. Annual Review of Cancer Biology, 1, 79-98. https://doi.org/10.1146/annurev-cancerbio-041916-065808 https://www.annualreviews.org/doi/10.1146/annurev-cancerbio-041916-065808
Lesser talked about causes of oxidative stress
Circadian Disruption
Pollution (noise, light air pollution)
Vigorous exercise
Alcohol
Image https://limewire.com/post/385039c0-5d6b-4fbf-ad48-49805497d6cc
The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes
The circadian system synchronizes daily with the day–night cycle of our environment. Disruption of this rhythm impacts the emergence and development of many diseases caused, for example, by the overproduction of free radicals, leading to oxidative damage of cellular components. Ref. Budkowska, M.; Cecerska-Heryć, E.; Marcinowska, Z.; Siennicka, A.; Dołęgowska, B. The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes. Int. J. Mol. Sci. 2022, 23, 14275. https://doi.org/10.3390/ijms232214275
Blue Light Damage and p53: Unravelling the Role of p53 in Oxidative-Stress-Induced Retinal Apoptosis
In the digital age, the widespread presence of electronic devices has exposed humans to an exceptional amount of blue light (BL) emitted from screens, LEDs, and other sources. Studies have shown that prolonged exposure to BL could have harmful effects on the visual system and circadian rhythm regulation. BL is known to induce oxidative stress, leading to DNA damage.
According to the authors, the findings of this study raise concerns about the long-term consequences of the current daily BL exposure and its potential involvement in various pathological conditions, including oxidative-stress-based retinal diseases like age-related macular degeneration. In addition, this study paves the way for the development of novel therapeutic approaches for oxidative-stress-based retinal diseases. Ref. Fietz, A.; Corsi, F.; Hurst, J.; Schnichels, S. Blue Light Damage and p53: Unravelling the Role of p53 in Oxidative-Stress-Induced Retinal Apoptosis. Antioxidants 2023, 12, 2072. https://doi.org/10.3390/antiox12122072
LIGHT POLLUTION: a systematic review about the impacts of artificial light on human health
This systematic review concluded that the increase in exposure to artificial light triggers mainly sleep and mood disorders, with light from electronic devices and artificial night the main source of pollution. Activation of oxidative stress is recognised as one of the pathways involved. Ref. Marli Do Carmo Cupertino, Bianca Thiengo Guimarães, José Flávio Giardini Pimenta, Leonardo Victor Lima Dutra Almeida, Lorran Nunes Santana, Thalia Azevedo Ribeiro & Yuri Nunes Santana (2023) LIGHT POLLUTION: a systematic review about the impacts of artificial light on human health, Biological Rhythm Research, 54:3, 263-275, DOI: 10.1080/09291016.2022.2151763
Alcohol, oxidative stress, and free radical damage
Alcohol promotes the generation of ROS and/or interferes with the body’s normal defense mechanisms against these compounds through numerous processes, particularly in the liver. Ref. Wu D, Cederbaum AI. Alcohol, oxidative stress, and free radical damage. Alcohol Res Health. 2003;27(4):277-84. PMID: 15540798; PMCID: PMC6668865. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668865/
Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review
The authors caution us that it is important to keep in mind that pathways implicated in alcohol metabolism, oxidative stress defense systems, inflammation, and neurodegeneration are under genetic control. Due to the genetic variability, one therapeutic approach may not fit all patients. Better understanding of underlying genetic factors regulating alcohol-related pathways may be the key to personalized treatment of alcohol use disorder (AUD). Ref. Tsermpini, E.E.; Plemenitaš Ilješ, A.; Dolžan, V. Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review. Antioxidants 2022, 11, 1374. https://doi.org/10.3390/antiox11071374 https://www.mdpi.com/2076-3921/11/7/1374
Implications of Exposure to Air Pollution on Male Reproduction: The Role of Oxidative Stress
In this study the authors touch on the clinical implications of air pollution on male reproduction while highlighting the role of oxidative stress. Ref. Omolaoye, T.S.; Skosana, B.T.; Ferguson, L.M.; Ramsunder, Y.; Ayad, B.M.; Du Plessis, S.S. Implications of Exposure to Air Pollution on Male Reproduction: The Role of Oxidative Stress. Antioxidants 2024, 13, 64. https://www.mdpi.com/2076-3921/13/1/64
Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases
This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. Ref. Daiber A, Kröller-Schön S, Oelze M, Hahad O, Li H, Schulz R, Steven S, Münzel T. Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases. Redox Biol. 2020 Jul;34:101506. doi: 10.1016/j.redox.2020.101506. Epub 2020 Apr 20. PMID: 32371009; PMCID: PMC7327966. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327966/
“Antioxidant/s” – what is in a name?
Image: AI generated by Picsart
•Using the term “antioxidant” to refer to substances is misleading. It is really a chemical property, namely, the ability to act as an electron donor. Some substances that act as antioxidants in one situation may be pro-oxidants—electron grabbers—in a different situation. https://www.hsph.harvard.edu/nutritionsource/antioxidants/
Looking Back at the Early Stages of Redox Biology
The most serious confusion came from the term antioxidants. Meanwhile this term is degenerated to describe something that is presumed to be good for human health. The idea that this perception is not simply biased may be exemplified by glucose, which is thought not to be good for human health and is (perhaps as a consequence) never called an antioxidant. As a polyol, however, glucose is an efficient free radical trap [201]) and, when metabolized, is the main source of reduced pyridine nucleotides, the small currency of redox biology, which guarantees defense against peroxide challenge and repair of oxidant damage.
A clear definition of antioxidants no longer exists. They comprise free radical trapping agents such as polyphenols, substrates of enzymes (e.g., GSH), which by themselves are poor or no antioxidants at all, and compounds that become constituents or cofactors of enzymes (e.g., selenium or zinc). Intriguingly, despite the heavy promotion of antioxidants in the lay press, controlled clinical trials in various “oxidative stress diseases” yielded overwhelmingly negative results (no or adverse effects) [89,342].
In short, in a biomedical context we do not need “antioxidants”, neither as scientific terms nor as dietary supplements to treat oxidative stress diseases. At best, we can expect a hormetic response from real antioxidants, which often share the tendency to act as pro-oxidants in vivo (see Section 6). Ref. Flohé, L. Looking Back at the Early Stages of Redox Biology. Antioxidants 2020, 9, 1254. https://doi.org/10.3390/antiox9121254
Potential harms of supplementation with high doses of antioxidants in athletes
Vigorous exercise generates large amounts of reactive oxygen species (ROS) as a result of the consumption of large volumes of O2 in athletes, causing some athletes to consume antioxidants in the erroneous belief that this will counteract the damaging effects of ROS. Ref. Li S, Fasipe B, Laher I. Potential harms of supplementation with high doses of antioxidants in athletes. J Exerc Sci Fit. 2022 Oct;20(4):269-275. doi: 10.1016/j.jesf.2022.06.001. Epub 2022 Jun 11. PMID: 35812825; PMCID: PMC9241084.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241084/
Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation
The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application.
Considering the positive and negative aspects of antioxidant modulation, it could be crucial in the future to identify new intracellular redox-related targets and to monitor in real time the “right balance” of ROS in each patient under the different conditions of disease and of therapeutic treatment in order to improve strategies for the prevention and treatment of human diseases. Ref. Nitti, M.; Marengo, B.; Furfaro, A.L.; Pronzato, M.A.; Marinari, U.M.; Domenicotti, C.; Traverso, N. Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation. Antioxidants 2022, 11, 1613. https://doi.org/10.3390/antiox11081613 https://www.mdpi.com/2076-3921/11/8/1613
Defense mechanisms and normal signaling
As research has progressed, it has become evident that antioxidants—especially in larger-than-usual amounts—may not always be beneficial. Large amounts of antioxidants may interfere with important functions in the cell, including its defense mechanisms and normal signaling. In addition, different types of antioxidants may not be interchangeable. Each of the many antioxidants found in the body has different properties. https://www.nccih.nih.gov/health/antioxidant-supplements-what-you-need-to-know
VIDEO: Oxygen, Stress, and Antioxidants (Ron Mittler, PhD) https://youtu.be/zFzAMQMzf5c
“Should We Be Scared of Reactive Oxygen Species?”
Video Description
Oxygen is essential for life, but it also has a dark side. In the presence of oxygen (that is abundant in our atmosphere) all cells can and do produce toxic compounds called reactive oxygen species. These compounds can attack proteins, DNA, lipids, and other cellular components and induce a dangerous state called ‘oxidative stress’. The damage caused by reactive oxygen species was blamed for aging, cancer and several other diseases, and a whole industry of antioxidants (for example, Vitamin C and E) emerged on the basis of this blame. In recent years however a complete overhaul of this concept is taking precedence, and numerous studies have shown that reactive oxygen species are required for life, acting as important regulators of many essential processes in different organisms. Examples for these include the immune response, proliferation of stem cells, and responses of cells to different stresses and pathogens. So, what should we believe? In this presentation, Dr. Mittler provided a balanced view of these two opposing viewpoints and showed by using different examples that, as with almost everything in life, balance is the answer.
EMFSA: When clearly indicated, antioxidants can play a role but as research indicates, it is a very delicate balance that can easily be disturbed with resulting adverse consequences. Simply taking antioxidant supplements to protect against 5G or EMF exposure is in our opinion not advised. Fresh, locally produced fruit and vegetables are wiser choices.