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  • Writer's pictureRyan Allen

Antioxidants and oxidative stress

There are many buzzwords in health and medicine, and the terms “antioxidants” and “stress” undoubtedly fall into this category. Among the general public, there seems to be the impression that antioxidants are unconditionally good. However, as I alluded to in a previous post on inflammation, there is almost never a definitive, binary “good or bad” situation when it comes to biological topics. We’ve seen that, while inflammation may be harmful in the pathology of various chronic diseases, it can also be quite beneficial in other circumstances. Now, let’s examine the case of antioxidants a little further to see why this too is not a binary issue, and why unrestricted antioxidant consumption may be more controversial than it seems.

Figure 1: Oxygen reduction from metabolism drives free radical formation. Metabolic processes such as the electron transport chain (ETC) donate an electron to diatomic oxygen (O2), which can eventually be converted to reactive oxygen species (ROS; denoted HO in this diagram). Note the unpaired electron on this molecule shown as a dot, causing reactivity that can lead to the harmful processes shown. (Image: Momtahan et al., 2019)

Antioxidants are substances that neutralize potentially harmful molecules known as free radicals, commonly showing up in our cellular metabolism as reactive oxygen species (ROS). Because of the instability of free radicals due to their incomplete electron pair, they tend to be highly reactive. As a result, these volatile molecules can cause damage by “stealing” electrons from other important molecules and cellular components, thereby disrupting their function. This is the phenomenon many often refer to as “oxidative stress.” When one chronically accumulates a large amount of free radicals, numerous pathologies can result from increased likelihood of significant cellular damage.

Figure 2: Generalized mechanism of atherosclerosis. Oxidized LDL particles and other fatty substances can accumulate on artery walls to form plaques, inducing inflammation and disrupting blood flow. (Image: Johns Hopkins)

Perhaps the most straightforward example in the realm of chronic disease is cardiovascular disease, where it is widely recognized that oxidized low-density lipoprotein (LDL) particles play a crucial role in the development of atherosclerosis. Oxidation of LDL can make the particle more susceptible to getting stuck in the artery walls, allowing it to form plaques and kick off inflammatory responses that disrupt vital blood flow.

The thought, then, is that ROS and other free radicals in the body are universally bad (and, consequently, antioxidants are universally good) because they can contribute to such pathologies. Though this may largely remain true, there are other crucial roles of ROS, such as in adaptive immunity, exercise response and hormesis, etc. In fact, numerous mouse studies and clinical trials with vitamin E and cancer suggest that supplementation with this antioxidant can actually promote tumor growth and metastasis. This supports the notion that a reduction in oxidative stress can favor cancerous cells more than healthy ones, perhaps because ROS can critically act as a signaling molecule when something is wrong, as in the case of cancer.

Some great work has been done on ROS signaling by Dr. Navdeep Chandel, Professor of Medicine and Biochemistry and Molecular Genetics at Northwestern University and author of the book Navigating Metabolism. He and his lab have detailed several pathways in which elevated levels of ROS regulate important biological processes, a field they call “redox biology.”

One example occurs in the pathology of cancer, in which mitochondrial metabolism and ROS have clearly been shown to be necessary for tumorigenesis. However, through this example we can begin to understand how these conditions do not present a dichotomy, but require a balance, or a moderation. I’ve previously alluded to some of the potential dangers of mitochondrial hyperactivity, but we all acknowledge that the solution is not to shut off the mitochondria entirely (for reference, this is the mechanism of cyanide poisoning). The same is true for ROS. While it can certainly be harmful in large quantities by upregulating/overproducing inflammatory cytokines, growth and proliferative genes, etc., there does appear to be a healthy homeostatic amount of ROS. Too little of this signaling molecule could result in conditions like immunosuppression with the inability to trigger proper immune responses or apoptosis, or failure to activate beneficial growth responses to stressors like exercise.

I must stress (no pun intended) that, for the majority of our 21st-century American society, the problem is not an overconsumption of antioxidants nor a lack of ROS. For the majority of the population, dietary sources of antioxidants are sorely lacking, and oxidative stress from free radicals contributes to the pervasive development of chronic disease. However, as with virtually everything, antioxidants are certainly imperfect; they are not silver bullets and should not just be consumed excessively. They are tools to aid us in achieving a healthy, homeostatic redox balance, not something to mainline with the goal of total free radical elimination.


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