Oxidative stress might not be the most dangerous form of cellular damage, but patients should take heed to protect themselves. While oxidative stress has long been recognized as a part of many pathologies, newer perspectives have started to see the utility of treating oxidative stress as a symptom in and of itself as a means of treatment. Damage caused by oxidative stress is implicated in a broad array of health conditions, including Alzheimer’s disease, autism spectrum disorder, chronic fatigue syndrome, depression, anxiety, and many cancers. For patients with these pathologies, gaining control of oxidative stress through therapeutic supplementation could be the key to experiencing relief from symptoms while preventing further damage. At the same time, healthy people may also benefit from reducing their level of oxidative stress as a result of its subclinical negative impact on the body; while healthy maintenance control is not yet in the mainstream medical consensus, there is reason to believe that lowering oxidative stress via glutathione supplementation could help patients optimize well-being. Understanding why this might be the case requires diving into the biological details of oxidative stress and exploring how the body reacts when its abilities to compensate for this stress are exceeded.
Oxidative Stress Drives Cellular Dysfunction
Oxidative stress is the process by which reactive oxygen species (ROS) produced by metabolic processes undergo chemical reactions with proteins, DNA, or lipids, which in turn inhibits the cell from making use of those molecules normally. The high-level impact of ROS reactions with physiological molecules ranges from carcinogenesis to tissue damage and dysfunction, potentially contributing to a wide variety of health complications. The physiological basis for why this is the case is far from simple, but medical science has begun to understand the most common risk vectors for oxidative stress.
Most patients are exposed to oxidative stress on a regular basis without any noticeable pathologies occurring. Nonetheless, the risks of oxidative stress are enduring, and patients can benefit from taking preventative action to protect themselves. Ultraviolet radiation, which deterministically causes oxidative stress at high levels in the event of a sunburn, is the most common source of oxidative stress. Cigarette smoke and alcohol consumption are important contributors, as both contain primary ROS in the mixtures themselves and also secondary ROS which are generated by the body breaking down the toxic chemicals in the mixtures. However, people who avoid getting sunburns and abstain from smoking or drinking alcohol still experience oxidative stress because normal aerobic metabolism is the primary source of oxidative stress. This means that patients simply cannot rely solely on good health habits to protect them nor can they assume that their levels of oxidative stress are low. Additionally, for patients who have health issues linked to oxidative stress, such as autism, the body’s ability to cope with the baseline level of metabolically-induced oxidative stress is totally insufficient. Patients with autism thus experience an abundance of oxidative stress-related symptoms like executive dysfunction and irritability as a result, as well as gastrointestinal issues like diarrhea. Meanwhile, patients with neurological conditions such as Alzheimer’s or Parkinson’s disease may see further neurodegeneration and subsequent loss of function as oxidative stress rises.
In the course of metabolism, the body breaks down energy sources, then uses a series of chemical reactions to synthesize molecules that cells can use for energy or for their essential functions. Some of these metabolic chemical reactions leave behind unwanted waste products in the form of ROS. Thus, higher metabolic activity generates more oxidative stress. In healthy people, the oxidative stress created by metabolism is tightly controlled by the body and minimal damage results. In fact, many endogenous molecules are synthesized specifically for the purpose of lowering oxidative stress and repairing the damage that it causes. These molecules are critical because if ROS are left unchecked, they readily cause damage to DNA and subsequently prompt mutagenesis.
To cause mutagenesis, ROS interfere with the DNA replication process by embedding themselves in the nitrogen backbone of the DNA molecule. When the cell attempts to copy the DNA, the ROS disrupts the process and introduces mutations where it is embedded. Error-checking the results of DNA replication typically catches these mutations and prompts the DNA damage to be repaired, but on rare occasions, it doesn’t detect the mutation. Uncorrected mutations can potentially lead to the rampant cellular growth known as cancer. This means that each ROS in circulation carries with it a very small chance of causing serious illness. When antioxidant molecules and DNA damage repair molecules are depleted or their synthesis is inhibited by malnutrition or an underlying medical condition, the reactive oxygen species balloon in number, and cells suffer.
When cells experience very high levels of ROS, their self-destruct mechanisms are triggered so as to prevent the ailing cell from causing damage to its neighbors through its malfunctions. For cells like neurons, the consequences of self-destruction can wreak havoc on the patient’s quality of life. Neuronal death is implicated in diseases ranging from Huntington’s to Alzheimer’s. For other cells, self-destruction is detrimental to the functioning of the tissue in which the cell resides. In liver tissue, dying cells leave the patient with a reduced ability to clean their blood of toxins, causing other downstream problems.
However, cellular damage can occur without causing the death of the cell. In the case of non-fatal cellular damage, ROS often react with enzymes, reducing their ability to catalyze chemical reactions that the cell needs to survive. This can have serious consequences for patients. Because the mitochondria are the organelle in which oxidative stress is the most likely to occur, it is the mitochondria which bear the brunt of enzymatic malfunction caused by ROS. As the mitochondria are responsible for producing the chemical energy that the cell needs to perform its job, oxidative stress that damages enzymes can reduce the efficiency of the entire cell. Liver cells, for example, might experience a decrease in their rate of blood purification, whereas neurons might find it more difficult to activate themselves and relay electrochemical messages to other neurons. Each of these outcomes results in poorer patient health.
Additionally, oxidative stress causes inflammation when uncontrolled. In the context of disorders like dementia, neuroinflammation is thought to be linked to cognitive dysfunction and deficiencies of the working memory. More broadly, inflammation tends to reduce the effectiveness of whatever tissue in which it occurs regardless of the initial cause. This means that oxidative stress could hypothetically reduce the efficiency of any tissue in the body which can experience inflammation; it also means that disorders which are aggravated by inflammation may benefit from therapies which reduce oxidative stress.
Oxidative Stress May be Necessary for Cellular Function
Given that oxidative stress is deleterious to cells, many patients are eager to reduce the amount of oxidative stress that their cells experience. However, using the metric that less oxidative stress is better for cells may lead to undesirable results; surprisingly, total prevention of all oxidative stress incidents may not be desirable. In animal models, for example, low levels of oxidative stress were found to improve lifespan. But research also shows that eliminating oxidative stress entirely via excessive doses of antioxidants ended up decreasing the animals’ lifespans. The explanation for this effect is relatively straightforward: much like the way muscle fibers cannot grow larger and stronger without first experiencing some tearing damage, small amounts of oxidative stress are necessary to keep various systems smoothly functioning. More concretely, researchers know that certain white blood cells use cached free radicals as part of the lethal cocktail that they deliver to bacterial pathogens. Without any oxidative stress whatsoever, these immune cells couldn’t do their job and the immune system as a whole would be weakened. There is evidence that other cells can make use of oxidative stress in similarly beneficial capacities. Despite this, there is no evidence that high levels of oxidative stress are beneficial, so there is still a strong scientific basis for reducing stress.
But how should patients go about reducing oxidative stress in a way that doesn’t leave them deficient in the baseline level of ROS that they need? Science lacks a definitive answer to this question at the moment, but there is reason to believe that there is a way forward nonetheless. Indeed, if patients could provide their cells with antioxidant molecules which the cells can use only as needed, there is a much smaller chance of completely depleting the necessary ROS. This means that the ideal antioxidant molecule would be something that the cells already use in that capacity. With this in mind, the antioxidant glutathione may be the best way for patients to address their oxidative stress issues without risking weakening their systems.
Keeping Oxidative Stress in the Healthy Mean
Glutathione is an appealing choice for patients seeking to reduce their levels of oxidative stress safely because cells already use glutathione prolifically. Animal, plant, fungi, and many bacteria synthesize glutathione from several essential amino acids and use it to defend themselves against oxidative stress by exploiting its ROS-receptive chemical structure. Because most life forms synthesize glutathione for themselves, it is often consumed in food, though it is not a nutrient. Stomach acids typically break orally consumed glutathione down into its constituent parts, which are later re-assembled by cells for the purposes of regulating oxidative stress. When cells detect high levels of oxidative stress, they traffic glutathione molecules to the problem area. Once there, glutathione reacts with the ROS, safely removing them from circulation and preventing them from damaging cellular machinery. Afterward, the cells traffic the newly oxidized glutathione molecule elsewhere to be recycled safely. Excess quantities of glutathione are safely stored in several different cellular holding vaults, preventing them from causing excessive reduction of oxidative stress.
Cells rely on glutathione as their first line of defense against oxidative stress, but in conditions of very high oxidative stress, glutathione supplies can run low and damage can occur. This means that providing a patient’s cells with an extra supply of glutathione via oral supplementation could mean the difference between experiencing oxidative stress damage and remaining healthy. However, increasing the proportion of glutathione’s chemical precursors in a patient’s diet doesn’t solve the problem; synthesizing glutathione from its precursors takes precious time, allowing oxidative stress to cause damage before the fresh glutathione can be brought to bear. Additionally, patients are unlikely to be able to anticipate when their body’s glutathione supplies are running low; glutathione levels are known to decrease with age and low levels associated with a number of serious health conditions. Significantly, insufficient glutathione supply has no early symptoms, though patients may soon experience symptoms of inflammation stemming from the damage caused by oxidative stress. Maintaining a larger supply of glutathione preventatively through supplementation is thus a good strategy for patients who want to avoid gaps in their protection.
Glutathione supplements currently on the market are readily used by cells to improve their ability to combat oxidative stress. Using sophisticated delivery systems, these supplements are guaranteed to reach where the body can use them, unlike with glutathione in food form. This can have significant benefits for patients; for example, research has shown that oral glutathione supplements can increase cellular glutathione concentrations by as much as 260% in immune cells and double the killing ability of certain immune cells responsible for handling viral infections. Glutathione is also highly tolerable and in clinical settings, most patients find that the side effects of such supplements are transient and mild. Of patients that report side effects, headache and minor nausea are the most common complaints.
While the clinical impact of glutathione supplementation is still under investigation, preliminary patient accounts indicate that it could reduce the intensity of all oxidative stress-related symptoms, which means that supplementation could be broadly applicable for a range of neurological diseases and gastrointestinal conditions, as well as autism, psychiatric disorders, and other pathologies. For patients with early-onset dementia, evidence suggests that a high-quality glutathione supplement might even reduce their oxidative stress levels sufficiently for the patient to experience an improved level of cognition. Future research will shed greater light on the details of how glutathione should be used clinically. In the meantime, patients who suffer from oxidative stress-associated conditions can be confident in the safety of glutathione as an emerging treatment that has the potential to significantly improve quality of life.
Allen J, Bradley RD. 2011. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med. 17(9):827-833. https://www.ncbi.nlm.nih.gov/pubmed/21875351
Dolbashid AS, Mohktar MS, Zaman WSWK, Basri NRH, Azmi MF, et al. 2017. Effects of oral glutathione precursors’ supplementation on human glutathione level. 2nd International Conference for Innovation in Biomedical Engineering and Life Sciences. 147-151. https://link.springer.com/chapter/10.1007/978-981-10-7554-4_26
Halliwell B. 2007. Oxidative stress and cancer: have we moved forward? Biochem J. 401(1):1-11. https://www.ncbi.nlm.nih.gov/pubmed/17150040
Lu SC. 2013. Glutathione synthesis. Biochimica et Biophysica Acta, 1830(5):3143–3153. http://doi.org/10.1016/j.bbagen.2012.09.008
Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, et al. 2007. Glucose
restriction extends Caenorhabditis elegans life span by inducing mitochondrial
respiration and increasing oxidative stress. Cell Metab. Oct;6(4):280-293. https://www.ncbi.nlm.nih.gov/pubmed/17908557
Segal AW. 2005. How neutrophils kill microbes. Annual Review of Immunology. 23:197–223. http://doi.org/10.1146/annurev.immunol.23.021704.115653
Yee C, Yang W, Hekimi S. 2015. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014;157(4):897-909. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454526/