On Retiring The Term; Antioxidant
Why it fails to accurately provide insight into the transfer of charge.
Antioxidant is a loaded term. It prevails within a lexicon where the notion of oxidation is implicitly branded as ‘bad’, while antioxidant is universally and almost unquestionably labeled as ‘good’. But this language not only fails to provide clear understanding regarding what oxidation truly entails in biology, it paints a picture to both the public and those within the sciences that the less oxidation, the better. This overly simplistic notion is baked in to the language we use to describe health and disease. Its conceptual insufficiency has proven anti-useful and has seeded fertile ground for marketers and snake oil salesman alike.
The term antioxidant gets thrown around by both the lay public and academics. But if push came to shove, I posit that very few would be confident in clearly defining what is meant by oxidation (and by association, antioxidants) while also being able to provide context for such a definition.
This can be seen in standard definitions of ‘antioxidant’:
“An antioxidant is a substance that can counteract or neutralize the damaging effects of free radicals, which are unstable molecules that contain unpaired electrons.”
Embedded implicitly into this definition are values1. Approaching biology using this terminology would lead one to thinking oxidation is always ‘bad’, and preventing said oxidation with antioxidants is by definition, ‘good’.
The unfettered ability to defend against the damaging effects of free radicals sounds great, however, free radicals are not in and of themselves, ‘bad’. In fact, free radicals signals appear to be the foundational network upon which cellular regulation and non-chemical communication rests. Without adequate oxidation, homeostatic coordination can break down. Oxidative stress is the signal for repair and adaptive self-organisation, without which, one could never heal from even the slightest of stresses. Perhaps one of the most salient examples of this notion is the beta-carotene trials of the 1980s.
Throughout the 1970s, increasing interest around the chemo-protective effects of plant compounds precipitated observational studies conducted on intakes of said compounds and specific health outcomes.2 In 1981, a paper published in the Lancet showed a clear, dose-response (higher validity evidence) relationship between beta-carotene intake and protection from lung cancer in smokers.
At the time, the understanding of disease and the ageing process was still in its infancy, with the prevailing view being the free radical theory of ageing. Findings such as these published in the Lancet on carotenoids fit perfectly with this idea due to their radical-scavenging properties. Off the back of this association, an interventional trial was planned and undertaken using synthetic beta-carotene supplements. The hope was that a simple pill could reduce cancer incidence by reducing the amount of oxidative stress within the body. Instead, the trial was terminated prematurely due to excess deaths in the trial (beta-carotene) group.
“Our results raise the possibility that supplementation with beta carotene may be harmful in smokers. The higher mortality due to ischemic heart disease and lung cancer among the beta carotene recipients requires more detailed analysis, and information from other studies is also needed.”
This story highlights the necessity of oxidation in homeostatic regulation and dynamic adaptation. Artificial dulling of the concentration of reactive oxygen species (ROS) via supplemental antioxidants (or locale-inappropriate dietary patterns) disturbs the very signals required for appropriate cellular responses.
The concept of an antioxidant is duplicitous. Under minimal scrutiny, one inevitably comes to ask the question, “If a molecule donates an electron to reduce an ROS, doesn't it then become a radical itself?”. After donating an electron, vitamin c, for instance, becomes the ascorbyl radical - a reactive molecule. In what sense then it's vitamin c really an antioxidant?
These reactions are redox reactions. Redox is a term that highlights that reduction (donating an electron) is always coupled with oxidation (loss of an electron). They are not independent processes. This makes the term ‘antioxidant’ troublesome.3 Molecules like melatonin do not have this precise issue, as its oxidized states also have reducing properties. This is one of the reasons melatonin is so intimately involved in stress responses and ROS/RNS as it has powerful reducing capabilities.
The importance of ROS in health and ageing links closely with the concept of hormesis. Colloquially, hormesis is known by, ‘what doesn't kill you, makes you stronger’. It is the idea that stressors of specific magnitudes can induce beneficial adaptations which ultimately increase the fitness4 and robustness of the organism. A problem we are facing in the modern world is that we are no longer exposed to enough appropriate stressors to adequately signal responses that increase robustness. Too much stress and the body can't keep up, too little stress, and the body becomes so frail that it can no longer withstand even the slightest of insults.
“Hormesis, an adaptive response, occurs when exposure to low doses of a stressor potentially induces a stimulatory effect, while higher doses may inhibit it... This has profound implications for promoting biological regulation at the cellular level and enhancing adaptability throughout the biosphere.”
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in inflammatory responses, where it exerts notable influence. It plays important roles in more late-stage oxidative states; in other words, it is not a first line defence against oxidative stress5. Increasing attention is being paid to the initiation of Nrf2 as it has been implicated in common disease conditions like atherosclerosis and cancer.6 Nrf2 is activated by oxidized thiol (sulphur) groups. If a sufficient oxidative load is produced, local and immediate redox factors are then supported by stronger players like Nrf2 and HO-1. This highlights the step-wise response we have evolved to efficiently manage the balance of oxidation and reduction. If there are only background levels of oxidative stress like a healthy person might be experiencing when fed and relaxed, there's no need to activate the big guns of the antioxidant system. However, after a 10km run or a tasty meal full of plant hormetic compounds, there might be a sufficient need to start producing more influential factors such as Nrf2.
Transcription factors and enzymes like Nrf2 and HO-1 have evolved to resolve imbalances in the redox system. If they were to be chronically suppressed, the body would never be able to mount an appropriate response to the collective stress that inevitably influences homeostasis. Chronic suppression of oxidation would disturb the signal that is ostensibly saying, “Something's wrong here, we need to adapt in a dynamic fashion in order to guide system-level fitness.” Studies examining the impact of chronic (continuous) NAC (n-acetyl cysteine) supplementation in rodent models have demonstrated that by artificially preventing the accumulation of oxidized thiol groups, larger orchestration of global redox balance is effectively prevented by insufficient levels of oxidative stress.7 In other words, continuous use of supplemental antioxidants could douse the strength of hormetic responses, leading to poorer fitness and health outcomes. Too little oxidative stress limits the mounting of beneficial long-term homeostatic responses.
It's clear oxidation is not inherently ‘bad’ and antioxidants are not inherently ‘good’, but we still occupy a landscape where these terms harbor implicit values. An alternative to the term ‘antioxidant’ must be devoid of connotation while simultaneously accurately portraying that oxidation always simultaneously occurs alongside reduction. The term, 'redox modulator', despite being literarily stale, satisfies both of these prerequisites. Instead of calling vitamin c an antioxidant, we could call it a redox modulator. This is technically more accurate and would not seed territory for marketers to sell products solely on the basis of an implicit value placed on a term like ‘antioxidant’.8
An alternative to the term ‘antioxidant’ must be devoid of connotation while simultaneously and accurately portraying oxidation as always occurring alongside reduction. The term, 'redox modulator', despite being literarily stale, satisfies both of these prerequisites.
The term, ‘redox modulator' allows us to understand the beneficial effects of exercise, red light therapy, sunlight, plant-hormetic compounds and cold thermogenesis despite the fact that they are all inherently stressors. They can provide notable benefits to health precisely because they are stressful. When in an appropriate dose and situation, hormetic signals shift the equilibrium of the system.9
While care has been made to avoid contradictions and half-truths in this article, it should be noted that true antioxidants (those not involved in redox reactions, but rather supply ‘free’, or labile electrons to the system) do appear to exist. Earthing (also known as grounding) facilitates the uptake of labile electrons from the Earth's surface into the body. These electrons can be stored and directed via the global semiconductive DC control system (and the fields that accompany it) to rectify perturbations in global redox balance. This appears to be the only case in which the term ‘antioxidant’ might be accurate and technically useful.
“Biology never stoops to a perfect correlation.”
-Nick Lane
When ROS/RNS are generated, their various chemical transformations release quanta of energy; biophotons. Biophotons are in large part (although not exclusively) non-chemical communicatory manifestations of reactive molecules relaxing back to their ground states, releasing photons of various wavelengths in the process. From a biological perspective, it seems logical that information regarding local and system wide redox balance be communicated via light; it's fast, and different wavelengths can ostensibly communicate diverse messages.
Recent research by Rhys Mould's group at the University of Westminster has elegantly furthered the discoveries of biophoton release in onion roots made by Alexander Gurwitsch in 1923. Mould's simple study demonstrated that signals from mitochondria are communicated via light to other mitochondria10. Apoptosis (among other regulatory responses) can be triggered by light signals from adjacent colonies of mitochondria separated in space; something not possible through chemical communication. The light signals are a direct result of metabolic activity and the coupled ROS/RNS production.
The salient point here is that redox modulators artificially alter the biophoton light show inside each of our cells11. These light shows are among the coherent substrata that facilitate the defining features of multicellularity; cooperation, identity and cohesive goal-directedness. This information is necessary to orchestrate global homeostasis via dynamic adaptivity in the face of stressors. If we lose coherent signaling by artificially influencing the ROS/RNS biophoton release, cells lose their traits of multicellularity. The implications of an incoherent communications system are pernicious; cells that no longer realise they are part of a whole. Cancer.
The godfather of marketing, Dave Asprey, has claimed he takes the powerful redox modulator, astaxanthin (among a laundry list of other supplements), every day for many years to improve his health. Does he know he might be disturbing his light show in a way analogous to our beta-carotene-takers from the Lancet trial? Bryan Johnson judges cacao based off its flavenoid (redox modulator) content. Does he think about the fact that this food ultimately imparts light information that may not be congruent with the other environmental signals he is receiving (cacao cannot grow in the conditions he is exposed to)? Perhaps they are both moving the needle in the right direction, but it is also possible that their enthusiasm for artificial and/or locale-incongruent redox modulators is preventing their bodies from responding appropriately to the host of stressors they encounter in their lives.
This idea calls into question the notion that we should always try to curtail inflammatory-driven processes like in colds and flu's or muscular/joint pain. The idea of redox modulation highlights the necessity of oxidation and thus inflammation in adaptive processes. Without oxidation, there is no resolution. Oxidation and the accompanying processes like biophoton release are the signal to repair and restore homeostasis. Dulling it through inappropriate use of redox modulators can scramble the fidelity of the message, preventing resolution. With this framework, it becomes logical to question whether taking vitamin c, elderberry, turmeric, black seed oil, spirulina, NAC, niacin or methylene blue when we are ill is helping or hurting in the long-term. Might it be better to simply enhance the fidelity of the signal by letting it play out unadulterated? I do not believe we have good answers to these questions yet, but it does highlight that when we use locale-incongruent redox modulators, we are playing with fire.
The retiring of the term antioxidant is a push to address pernicious biases in our lexicon that inhibit our ability to understand complex and nuanced topics. The term, redox modulator allows both scientist and lay people alike to approach the topic with a greater understanding of the bilateral response dynamics that predominate the world of biology. The labeling of something as ‘good’ or ‘bad’ is limiting in its very nature. Balance and harmony are concepts of supreme importance in ancient traditions. It is time we embrace the context-dependency that underpins not only redox, but biology as a whole.
Summary
Antioxidant as a term is poorly defined. It is used by both lay people and academics alike with little to no regard of the nuance that underpins the roles and necessity of oxidation in biological systems.
Antioxidants are duplicitous. Vitamin c can be oxidative in nature. Once an antioxidant donates an electron, it becomes an oxidant itself as it seeks an electron to replace the one it’s just donated.
Going forward, a more accurate way to speak about the transfer of charge might be 'redox modulator'. This term presents no implicit bias and accurately portrays that both oxidation and reduction are occurring simultaneously.
Earthing provides us with labile and storable electrons from the Earth’s surface; a ‘true’ antioxidant’, as these electrons are not involved in redox reactions.
Oxidation is necessary; without the ability to mount an oxidative (inflammatory) response, we would succumb to diseases of severed communication. Without the capacity to signal local information, there is a transition from organic disease to chronic disease.
Biophotons are a primary basis of non-chemical communication. Artificial or locale-incongruent interactions with redox modulators ultimately alter the light show within us, shaping communications. This could be used in a way that is net positive or net negative. Knowing which way you might be moving the needle is difficult.
The subtlety with which values are subverted into scientific concepts should be concerning. Not only can these ideas become embedded into general verbiage, they can potentially influence scientific investigation and the distribution of limited resources and funding. We have seen this play out in the monopoly nuclear genetics has had over mitochondrial genetics in disease research since Watson and Crick laid claim to the notion that all the secrets of life were to be found within the double-helix. This subtle value placed on the contents of the nuclear genome has not only limited progress in the understanding of disease and ageing, it has prevented the exploration of other potentially fruitful ideas. Language can contain implicit connotations that influence the ways in which we engage with it. It is particularly important in the sciences to recognise the meaning between the words and how such meaning can undermine nuanced concepts.
It goes without saying that epidemiology without logic and inductive reasoning almost certainly commits research to ill-conceived premises; the outcomes of which are by definition, anti-useful. I've commented on this at length in previous articles: Building A New Philosophy Of Health and The Bryan Johnson Fallacy.
It should be noted that not all reactive molecule are equal in their potential effects. The hydroxyl radical is the most reactive ROS, capable of generating oxidative chain reactions that transpire on the femtosecond scale. Trading a hydroxyl radical for an ascorbyl radical, for instance, is probably a good idea and a net benefit for the system.
Here I am using fitness in the Darwinian sense where it broadly translates to ‘most likely to survive’; more suitably adapted to thrive in one's given environment.
For more information about the relationship between Nrf2, HO-1, oxidative stress and fitness, see Nick Lane's “Oxygen”. This book is a tour de force in systematically examining the nuances of oxidative metabolism's relationship to ROS and disease.
Nrf2 and other transcription factors involved in oxidative stress are discussed in the literature as double-edged-swords, having both potentially positive and negative effects on disease processes. This duality speaks to the importance of context. Just as with the carotenoid studies of the 1970s, the harm or benefit is determined by a litany of co-occurring factors.
NAC is a widely used over-the-counter supplement. It can have remarkably beneficial effects in a variety of situations, however, chronic use of such a compound with the ability to powerfully modulate global redox could absolutely come at a cost to health.
It may seem nit-picky to emphasise the role of word selection in the sciences guides marketing and advertising. However, given the largely unrelated nature of the supplement industry and it's collision with the exponential rise in chronic and ‘incurable’ illness, there has opened an enormous opportunity for marketers and business people to take advantage of vulnerable individuals by using buzzwords to peddle false promises. Careful and considered use of language is vital in the lexicons of both scientific and lay people to prevent insidious product creation and marketing. Marketers rely heavily on boiling down highly complex and nuanced topics to catchphrases and buzzwords. The use of appropriate language and word choice could change the way we seek solutions; not only as individuals, but also in the sciences.
The concept of redox and homeostasis bare remarkable similarities with non-equilibrium thermodynamics. Redox modulators play important roles in energy dissipation and maintaining a stable state far from equilibrium; this is why access to plant-hormedic compounds, for instance, are so tightly coiled with other environmental conditions. I will be examining this notion in greater detail in an upcoming article.
This process undoubtedly occurs all throughout the cell, not just in the mitochondria. However, most of the ROS/RNS emanate from the oxidative metabolism of the mitochondria.
It should be noted that this artificial alteration can be used to systemic benefit too. Supplemental redox modulators can absolutely be helpful, but the devil is in the details. The question really is how do you know where the effect might be net positive or net detrimental? We currently do not have sufficient understanding in this area in my opinion. Biophoton imaging presents the most promising diagnostic tool in this area.