Mitohormesis and antioxidants: the upside of stress
the essential role of transient stress in our body and the broader lessons from mitohormesis
Oxidative stress (an excessive load of reactive oxygen species (ROS)) is associated with many disease states in human beings. Therefore, it would seem logical that antioxidants that can react with and neutralise ROS should improve human health. Furthermore, there is substantial evidence linking the consumption of fruits and vegetables with a reduced occurrence of disease, which is often attributed to their antioxidant effects. However, there is no evidence that antioxidant supplementation reduces disease or mortality. In fact, there is mounting evidence that antioxidant supplements can harm us. For example, “treatment with beta carotene, vitamin A, and vitamin E may increase mortality”1.
Why is this the case? Although plant-based foods are undoubtedly beneficial to us, their benefits are likely due to the phytochemicals in them that trigger a hormetic response. Hormesis is the process by which low doses of stressors lead to beneficial adaptations that benefit the system rather than harming it. And it seems that ROS exposure also triggers a similar response known as mitohormesis. The relationship between ROS exposure and disease/mortality follows a J-shaped curve as illustrated below2.
Mitohormesis explains why physical exercise and caloric restriction are beneficial even though they both produce significant amounts of ROS. In fact, antioxidant supplementation before a workout negates the health-promoting effects of exercise3. But why is the response to oxidative stress hormetic in nature? The answer to this question illustrates some principles that are applicable in complex adaptive systems across domains.
Stress is a signal that triggers a systemic response
Reactive oxygen species (ROS) are “essential, health-engendering signaling molecules”4 produced by mitochondria in response to stress. This signal triggers stress defense mechanisms that not only detoxify the ROS themselves but also trigger other stress defense pathways. If we suppress the signal, then we also suppress this broader systemic adaptation.
Transient stress improves steady-state outcomes
The systemic adaptation to transient stress makes the system more resilient in the steady state i.e. “transiently increased ROS levels act to induce a vaccination-like response within the individual cell to lead to reduced ROS levels and better stress defense in the steady state”5. The systemic and broad-based nature of the adaptation provides protection not just from exposure to ROS but also from other exogenous and endogenous stressors.
The stress signal is multi-functional
As the image below shows, ROS signalling is essential to a whole host of basic biological processes6 and “a basal level of ROS in cells is essential for life”.
This is not surprising given that the evolution of aerobic life itself occurred after the appearance of ROS which “were most likely first used by cells as signaling molecules to sense unsafe levels of atmospheric oxygen, or to monitor different metabolic reactions, but have since evolved to regulate almost all aspects of life in plants, animals, and most eukaryotic organisms”7.
In complex adaptive systems, many components and processes are multi-functional and we should think twice before suppressing any component or process even when they cause harm. A similar error is the avoidance of sun exposure due to the risk of cancer. There is significant evidence that vitamin D supplementation cannot substitute for the cardiovascular benefits of sunlight (which probably arise from the role of the ultraviolet-induced release of nitric oxide from the skin).
Don’t nip it in the bud
So how can we intervene to limit oxidative stress without hampering either the vaccination-like systemic adaptation or its role in signalling? The answer is somewhat counterintuitive and runs counter to the dominant philosophy of modern science and the technocratic instinct - “strategies aimed at removing the damage incurred, rather than directly inhibiting the damaging agent, may ultimately prove most effective”8.
In other words, the resilient approach is to target the damaging consequences of the stress rather than nipping the source of the damage in the bud. In the case of oxidative stress, this would involve stimulating autophagy to clean up the damage done. But the principle is applicable in many other domains. For example, river floods are stressful events for human beings but they are also fundamental processes. Rather than suppressing floods by limiting rivers to a narrow channel, flood control should leave “room for the river”.
Similarly, the failure of businesses cause stress to the macroeconomic system but the threat of firm failure is also a fundamental component of a functional economic system. The economist Joseph Berliner called this the ‘invisible foot’ which needs to be “applied vigorously to the backsides of enterprises that would otherwise have been quite content to go on producing the same products in the same ways, and at a reasonable profit, if they could only be protected from the intrusion of competition”. Therefore, macroeconomic interventions and safety nets should protect individuals rather than bailing out firms e.g. the Danish ‘flexicurity’ model that tries to protect individuals rather than preserve jobs.