Oxidative stress has been defined by the National Institutes of Health (NIH) in the U.S. as “a condition that may occur when there are too many unstable molecules called free radicals in the body and not enough antioxidants to get rid of them. This can lead to cell and tissue damage.” (1) There is a growing body of evidence that oxidative stress is heavily involved with, and responsible for, disease onset and progression, but can potentially be mitigated—at least partially—by whole plant foods. Whole plant foods can be defined as minimally processed plant foods such as fruits, vegetables, grains, legumes, nuts and seeds, and herbs and spices (2). Understanding the interplay of nutrients supplied by whole plant foods and oxidative stress pathways, both systemically and at the cellular level, is a frontier that is still only partially understood. In this paper we explore these important functions.

Altering plant-foods from their original forms is not a new concept, as humans have preserved foods through methods such as cooking, drying, salting, fermenting and freezing for centuries. Modern introduction of food processing strips away or extracts components of the whole food, transforming the original into a manufactured “food-like” substance, something that is potentially unrecognizable to the organism or its gut microbes. Altering whole plant foods potentially removes fiber, and destroys antioxidants, diminishing the nutritional value of the final products from a perspective of oxidative stress reduction. Processing of foods can be done to varying degrees, such as refining grains to create flour. If the whole grain is used, the flour may retain many of the benefits of the original, but when a grain is separated into component parts of endosperm, germ and bran, and only the endosperm portion is used to create flour, nutrients and fiber are stripped away. Other examples of processing include removing sugar from beets, or extracting oil from peanuts. Many of the antioxidant and trace elements obtained from fruits and vegetables can be found in the skin which is typically removed in the course of processing, with much of the fiber. The processed food is left with calories, but without antioxidants to reverse the oxidative stress induced by manufacturing of ATP. During electron transport a 1–5% rate of errors occurs in transferring the electrons between cytochromes causing formation of a superoxide free radical, most commonly at cytochrome I and III. When the organism experiences greater stress, this error rate and additional pro-oxidant production in the mitochondria increases significantly (22). In a redox balanced organism there is sufficient superoxide dismutase (SOD) and other free radical scavengers to neutralize the impact of errors in electron transfer so they do not cause ongoing problems in management of free radicals. But when the supply of antioxidants has been depleted injury can occur. Thus, foods with calories but without antioxidants push an organism’s normal physiology towards a pro-oxidant, pathophysiological state that can result in cellular and organ damage.

Energy production through metabolism of the fats, proteins, and carbohydrates contained within ingested animal products (which lack fiber and significant amounts of antioxidants) creates a pro-oxidant environment, similar to what occurs after ingestion of processed foods (39). Unfortunately, with regular consumption of animal products, there are deleterious alterations to the gut microbiome and other mechanisms in place that increase oxidative stress in the consuming human. Examples include the production of TMAO [trimethylamine N-oxide (79)], higher concentration of branched chain amino acids (80), contamination of the meat/fish with PCBs (81), and harmful heavy metals such as lead and mercury (14), in addition to other toxins that contribute to a heavily pro-oxidant state.

There are a host of other non-dietary factors that positively or negatively affect one’s oxidative state. Positive factors include, but are not limited to exercise (82), sleep (83), hydration (84), vitamin D level and mode of delivery (85), and loving relationships (86, 87). Negative lifestyle choices influence levels of toxin intake through smoking (88) and ethanol use (89), as well as prescription drug use or other substances activating the liver’s P-450 enzymes (22), psychological stress (90), severe life stressors (91), fasting (92), and other mild stressors (hormetic stress) which induce vitagenes resulting in increased endogenous antioxidants, as well as others (93).

We propose a “Triple Oxidant Sink” framework for addressing oxidative stress that uses an analogy of a triple basin sink with a faucet or inlet that fills one sink with water (78) (Figure 1). In this model, water represents oxidants that are produced or provided to an organism. These oxidants include free radicals of reactive oxygen species (ROS) and reactive nitrogen species (RNS), pro-oxidants of H₂O₂ and others. The triple oxidant sink theory has previously been described (78). Using the sink analogy, the sinks may all start at empty or low levels—representing a balanced and healthy organism. If there is a small amount of oxidant introduced, the sink can contain the water/oxidant easily, especially if the drain is functional. But if the drain is not working, and either the slow trickle continues indefinitely or the water inflow volume is increased, the first sink may fill and then start to overflow into the second. In this analogy, when the water flows into the second sink, disease occurs. The disease that develops depends upon genetic predisposition, much like type 2 diabetes or Parkinson’s disease. If the water overflow continues into the second sink and it does not drain, the second sink fills and overflows into the third sink. At this point complications of disease occur and ramify. Various factors influence how quickly the sinks fill, for example, the depth, size of the drains, and the amount of water flowing into the system. In the organism’s case, the depth of the first sink—where the oxidants are dumped—is determined by the endogenous antioxidant capacity (enzymatic and non-enzymatic) and the available exogenous antioxidant capacity. This endogenous level can differ between individuals based on the amount of genetically-determined antioxidant capacity. The oxidative state, at any given time, may be different based on variables which affect redox balance including the factors mentioned above affecting the oxidative state.

When a severe stressor presents in the form of infection (such as COVID-19), severe trauma, or life threatening sepsis, the oxidative sinks fill significantly. If the sinks are already fairly full of oxidants and a new oxidative stressor fills each succeeding sink, the likely result is an overflow of the sinks onto the floor. The organism is overwhelmed with pro-oxidants that cannot be fully eliminated and a cytokine storm ensues and the organism may end up on the floor as well!

This concept may explain why those with comorbidities have poorer outcomes with COVID-19 and with trauma. The prefilled oxidant sinks are overwhelmed with the inflammatory fallout of the infection or trauma and severe consequences ensue with acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and systemic inflammatory response syndrome (SIRS). It also could explain differential outcomes in both COVID-19, trauma, and other oxidatively stressing occurrences. Similar age patients may have totally different outcomes from the infection or similarly severe traumatic event. This may even explain why a late teen-aged college student could develop SIRS when the expected outcome would be benign due to their relative youth. Picture the quintessential college student who stays up multiple nights in a row studying for finals, eating only low-quality junk food and drinking only caffeinated sodas. Then they go on Spring Break and experience additional lack of sleep, significant alcohol (and possibly other pro-oxidant substance) intake along with a continued low quality diet and poor healthy fluid intake. The gut microbiome is shifted to an unbalanced, compromised state, leading to oxidant sink filling. An untimely exposure to COVID-19 could potentially result in severe sickness and even SIRS. In this situation, lifestyle factors compound the impact of infection to compromise redox balance and resilience.

A similar inflammatory situation occurs when a patient undergoes surgery. There is an inevitable increase in oxidative stress from the tissue injury during surgery leading to activation of IL-33 with subsequent mast cell activation. There are pro-oxidants that are added from the medications used for anesthesia. If this triple oxidant sink theory is correct, in a setting of a high baseline oxidative state adding to this additional stress, complications of surgery would be expected to skyrocket.

The goal is to empty the oxidative sink so that disease does not occur due to a redox imbalance and then, if another oxidative stressor should occur, the oxidative sink has capacity to stem an overflow and prevent the cytokine storm seen in severe COVID-19, sepsis, and trauma. Questions about this theoretical model include: how fast could the redox state be changed in an ideal situation? Is it possible to reverse the systemic inflammatory response by emptying the sinks? Is it possible to reverse the diseases and the complications of disease by emptying their respective sinks if permanent damage has not occurred? Obviously an antioxidant based whole plant food diet is not the only factor in helping achieve redox balance, but it is a major factor that can be altered in one’s lifestyle (78). More research is needed to address these questions and provide evidence for our model.

The majority of known mechanisms for determination of health and longevity involve oxidative stress and the improvement of the organism’s redox balance. These mechanisms include FGF21 (94, 95), mTOR signaling (96), telomere length (97, 98), TMAO (79), increased proportion of branched chain amino acids (80), and others.

Based on the evidence we have discussed in this review, oxidative stress appears to be a major contributor to disease processes. Whole plant food derived antioxidants and fiber (in the background of a healthy gut microbiome) serve as significant mediators in the ability of the body to maintain redox balance. Thus, using whole plant foods as medicine along with maximizing positive lifestyle behaviors, and minimizing foods and activities depleting antioxidant reserves should lead to a balanced redox state. When redox balance is achieved, oxidative stress related diseases can be avoided, ameliorated, and possibly reversed. There is still a need for research to better understand how diet and lifestyle impact redox balance. Areas of research focusing on the triple oxidant sink and food as medicine could include redox balancing in infection, such as COVID-19 and other viral or bacteria-induced illnesses. Trauma and ICU settings have severe oxidatively stressed patients who would likely benefit greatly from redox balancing with appropriate medicinal whole plant foods. Almost every patient entering an emergency department (ED) has redox imbalance problems. Would it be reasonable to treat a patient coming into the ED with lung disease and COPD exacerbation with a breathing treatment and whole plant antioxidants and fiber (rather than a cheeseburger, fries, and a milkshake)? How might outcomes change if patients receiving a stent for a myocardial infarction were introduced to a whole plant food diet? We suggest that understanding the value and interplay of redox balancing, using food medicinally and incorporating other antioxidant behaviors, is key for optimizing nutrition and health.

DC: Writing – review & editing, Writing – original draft. CT: Writing – review & editing. CW: Writing – review & editing.