Reactive Oxygen Species and Antioxidants: An Alternative View

Antioxidants have been peddled as a cure-all for many pathological conditions including cardiovascular disease, diabetes and cancer. Additionally, there is a current theory that antioxidants can aid in forestalling aging as they directly inhibit the “Free Radical Theory of Aging.   The concept of antioxidants as efficacious aids in battling the aforementioned diseases and slowing the process of aging holds some merit on a superficial level.  However, when the science explores beneath the surface we find there are major flaws in the basic premise. Therefore, the purpose of this article is to provide a deeper understanding of the redox system in our body and examine the role antioxidants and reactive oxygen species (ROS) have in normal physiology with a focus on insulin resistance.

What are Antioxidants?

Oxidation reactions transfer electrons or hydrogen from a substance and can produce free radicals.  These radicals can then in turn start a chain reaction in which more chemicals become oxidized.  Antioxidants are molecules that inhibit the process of oxidation by “sacrificing” themselves by becoming oxidized. Vitamin E for example is an antioxidant that stops the chain reaction of lipid peroxidation that is detrimental to lipoproteins.

We have two main components of our antioxidant system, the endogenous and exogenous. The endogenous system, produced by our body, which consists of gluthatione, glutathione peroxidase, superoxide dismutase, and catalase.  The exogenous system, put simply, includes those derived from dietary sources including vitamin A, E, and C.

Vital role of ROS in Cell Signaling

While ROS are highly reactive and have the ability to cause chemical damage, they are critical in proper cell signaling. ROS are the products of normal metabolism and can beneficial as well as harmful(1). Therefore, it is naïve and superficial thinking to make a blanket statement that ROS are harmful and ought to be eliminated In fact, recent papers have highlighted the vital role they play as intermediates in cellular signaling pathways (1,2).  The literature indicates that ROS play a role in ensuring proper cell signaling, function, and adaptation. A full review of these functions is beyond the scope of this article, however, I will touch on a few key roles ROS play in cell signaling.

ROS and Insulin Resistance

One of the main sources of cellular ROS is the mitochondria (3).  In a state of hyperphagia and chronic nutrient/energy overload, what we call obesity) we increase the flux of nutrients through the mitochondrial electron transport chain (ETC) increasing the production of the ROS O2Ÿ and eventually H2O2.  H2O2 can inhibit the cell signaling of the insulin receptor by blocking the pathway between insulin-receptor substrate 1 (IRS-1) and PI3K, thus inducing insulin resistance (IR) (Figure 1.).

Mito

Figure 1. Mitochondrial production of ROS and impaired insulin signaling

What makes this scenario interesting, and troublesome is that ROS and changes in cellular chemical conditions from normally functioning mitochondria promote mitochondrial biosynthesis and reduce insulin resistance, whereas ROS from mitochondrial dysfunction due to nutrient overload promote insulin resistance (3,4). Insulin resistance due to mitochondrial overload may actual be a cell survival mechanism as extremely high levels of ROS signal apoptosis.  As Chris Masterjohn made a case for this concept in is talk at AHS 2013, obesity induced IR from this mechanism is how our cells communicate that we need to stop “cramming” the mitochondria full of nutrients.  In this regard, it is of no surprise that research regarding the use of antioxidant therapy is equivocal.  I would hypothesize that immediate improvements in insulin resistance through antioxidant supplementation would be short lived as they would promote nutrient flux through the mitochondria and restore the ROS induced insulin resistance.  This hypothesis would explain why the clinical trials examining the efficacy of antioxidant therapy improving insulin sensitivity in type 2 diabetes are equivocal.

ROS as a “Hormetic” Stress

As with all biological organisms, our cells adapt to stress. If the stress is too low there will be no pressure to adapt to the stress. If the stress is too high the cell will be unable to adapt soon enough and cell death with occur. If the stress is in the right amount, there will be beneficial cellular adaptations, a term now referred to, aptly enough, as hormetic stress or the “Goldilocks Phenomenon” (5).  The redox status of the cell, particularly the level and type of ROS present, can serve as a type of stress that induces cellular adaptations, including beneficial adaptations. This idea holds true in regards to oxidative stress in which some ROS promotes adaptation while too much promotes pathology.

Preventing normal ROS levels from consumption of vitamin C has been shown to reduce positive cellular adaptations, mitochondrial biogenesis, that occur due to increased ROS that arise during exercise (6,7).  Additionally, exogenous antioxidant therapy has been shown to suppress beneficial adaptations of the endogenous antioxidant system and the insulin sensitizing effects of exercise (8).  Taken together, this evidence clearly indicates ROS are critical in conveying messages of what is occurring inside our cells and manipulating that signal through large doses of antioxidants may in fact be deleterious to one’s health.

To explore this idea further I must refer to an artfully written paper on the topic of metabolic flexibility for it does the topic more justice than I can (9). I have presented a figure from the paper that I feel displays the ideas in this post succinctly (Figure 2.).

 hormetic

Figure 2. adapted from Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

In Summary

Antioxidants, as with most supplements, have been proclaimed to be a cure-all for many pathological conditions including cardiovascular disease, diabetes and cancer.  This idea is based upon the notion that ROS are deadly and life threatening (in terms of cellular life). Unfortunately, the critical role ROS play in cell signaling was initially overlooked as antioxidants were so highly touted.  Yes, I do believe antioxidants can be beneficial in maintaining proper health as many individuals do indeed have the antioxidant vs. pro-oxidant scale tipped in the favor of pro-oxidants. I would also argue that providing our body the necessary substrates to bolster our endogenous immune system would be the most appropriate way to increase out antioxidant capacity. I draw this conclusion for sever reasons. The first is that I believe in most cases our body knows how to maintain the redox balance more elegantly than our minds do. With adequate substrates we will manufacture what we need when we need it. Second, relying heavily on exogenous antioxidants such as vitamin C does not place our endogenous system under a hormetic stress, effectively repressing those pathways responsible for endogenous production (i.e. Nrf1/2). I close with stating that, as is becoming a common theme on this sight, one must careful analyze why you are taking antioxidants and if they are truly necessary.

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