Stress is Necessary: The Hormesis Hypothesis
Summary
Hormesis is the response to a stressor that can have a positive effect on the body. Instead of suffering traumatic damage, the cells respond and adapt, allowing them to better respond to stressors in the future. Caloric restriction and exercise are two well-studied processes that induce hormesis.
What is Hormesis?
Hormesis is a biological process where a low dose of a stressor induces an adaptive, beneficial effect but is damaging at higher doses.1 This process can occur at multiple levels within the body, including at the cellular, tissue, and system level, with biological and neurological systems optimizing functions to respond to changing environments or exposures. In less than a single lifetime, the human organism can perform small but useful rapid evolutions to combat unique threats in its environment. The level of threat exposures is key. Exposure to threats, toxins, or adversities creates biologically stronger organisms when it is not too much or too little. This process is called hormesis.
The original concept of hormesis was first introduced in the 16th century by a Swiss physician named Paracelsus who suggested that the dose is what determines if something is a poison.1 In 1943, the term “hormesis” was introduced by scientists to describe the beneficial effects of a treatment or exposure at a certain level that is harmful at a higher intensity or exposure.2 In other words, sublethal exposure to a stressor induces a response in the body that results in stress resistance.2 Exercise is a good example of hormesis at work in the body. The average person would likely experience pain, inflammation, and oxidative stress if they ran a marathon with no training. But, if instead they engage in an exercise routine that puts appropriate stress on their body including their muscles and lungs, eventually they will get stronger and be able to run a marathon without extensive damage to their body.
The concept of hormesis originated in the field of toxicology, but it has since been determined to be applicable to other areas including oxygen concentration (hypoxia), extreme heat or cold, starvation, over-nutrition, pain, xenobiotic exposure, environmental stress, and pathogen-stimulated immune adaptation.2,3 A hormesis database from 2005 lists over 5600 dose-response relationships among 900 chemicals and physical agents.3 A biological phenomenon can be labeled as a hormesis process if:3,4
- It demonstrates a two-phase dose-relationship where the response to low dose is opposite the response to a high dose
- The concentration and effects of the low dose are measurable, not simply a placebo effect
- Factors acting on the biological system are present in the natural environment
Hormesis involves the biological concepts of conditioning and adaptation to exert its beneficial effects.1 Conditioning and adaptation are often used interchangeably to describe the idea that low levels of stress stimulate or upregulate existing cellular and molecular pathways to improve the capacity of cells and organisms to withstand greater stress.1,2 At the cellular level, pathways that allow cells to adapt include the protein quality control system, hormone release, endoplasmic reticulum stress, and mitochondrial adaptation.3 These systems coordinate the actions of transcription factors, microRNAs, heat shock proteins, cellular messengers, and enzymes including those involved in antioxidant pathways, DNA methylation, and DNA repair to allow the cell to respond and adapt to the stressor.3
Most physicians agree that the human body can produce healthy, productive biological responses in the face of toxic, dangerous, or overly taxing environments. Hormesis is not a superpower; it is a survival mechanism. The best way to embrace the gifts of the hormesis cycle is not to undergo unbearable trauma. Rather, it is to establish a lifestyle that maintains a consistent, healthy balance of a variety of stressors.
The Biological Importance of Stress
Stress, despite the discomfort it brings, is vitally important for creating and maintaining healthy biological and neurological processes. It facilitates a necessary physiological resiliency. However, in the 21st century, technology and progressive economic structures have made incredibly low-stress lifestyles available for the first time in human history. This can prevent the body from developing important stress-resistance pathways.
Stressors can be thought of as healthy challenges or obstacles that an organism must overcome, but to do so, that organism must improvise and improve. Stress, in this context, is not the same as anxiety. Anxiety and other forms of unnecessary adrenal stimulation do not qualify as healthy stressors. These processes create unnecessary friction in the body’s most important systems and can create and exacerbate devastating health problems over time. Embracing hormesis in the modern age has nothing to do with seeking out experimental or dangerous levels of toxicity.
Hormesis can also be thought of as the body trying to maintain its own homeostasis.5 When a stressor disturbs this balance, the body must adapt to return to its previous state, and this allows it to better handle the stressor in the future.5 If the stress is too mild, it does not force the body to respond and adapt; if the stress is too extreme, it can overload the body and cause damage.5
Diet
For thousands of years, humans were either relentless hunter gatherers or brutal agriculturalists. However, in the last century or so, extreme advances in technology and sociology changed the way humans approach food, often making it much easier to obtain food than it was for human ancestors. These changes may be bypassing hormesis pathways that were previously important to prepare the body to find and consume food. On the other hand, caloric restriction can work as a beneficial stressor on the body and improve health and longevity. Scientific studies have observed a positive effect on multiple facets of health when calorie intake is reduced to about 20 to 50 percent of normal intake, including improved insulin sensitivity and metabolic health, decreased incidence of cancer, and increased longevity.5 This reduction causes a low-dose stress response in the cell, activating multiple major signaling pathways, including Nrf-2, NF-κB, Akt, and PGC-1α signaling, which causes it to adapt and ultimately results in cardiometabolic protection.5
Exercise
During exercise, various stimuli can stress the body and disturb homeostasis, including changes in body temperature, metabolism, and oxygen availability and increased oxidative and mechanical stress.1 In response to exercise, cells produce and release messengers including reactive oxygen species (ROS), reactive nitrogen species (RNS), calcium, growth factors, cytokines, and eicosanoids.1 These cellular messengers activate various signaling pathways which can control gene expression and lead to an adaptive response in multiple tissues of the body.1 The right amount of exercise can help reduce the risk of many diseases and increase overall health and wellness. However, at the cellular level, excessive exercise can result in prolonged production of oxidative species and inflammatory mediators, overwhelming endogenous defense mechanisms, stimulate the breakdown of proteins in the body, impair protein synthesis, and result in muscle weakness and atrophy due to insufficient recovery.1
Most people are probably familiar with exercise-induced hormesis, even if they are not familiar with the scientific terminology. In the case of lifting weights, the body responds to the stress of muscle damage by building stronger muscle fibers and accumulating muscle mass over time. For cardiovascular activities such as running or biking, athletes will find their endurance and capabilities increase over time as their lungs, heart, and other metabolically active organs adapt. Other examples of adaptations to exercise include:1,4
- Mitochondrial biogenesis and adaptation
- Remodeling and hypertrophy of skeletal muscle
- Upregulation of antioxidant network
- Cardiac protection
- Heat tolerance
- Adaptation to low energy substrates (low blood sugar)
- Muscle hypertrophy in response to blood flow restriction
Another aspect of exercise that demonstrates the hormesis process is intestinal permeability.6 After exercise, intestinal permeability increases according to the intensity and duration of the exercise with subsequent gut barrier disruption occurring for several hours after intense exercise.6 However, research in chronic exercisers indicates a protective effect with improved gut barrier integrity.6 This specific effect is thought to be mediated through heat shock proteins (HSPs), that work in cells to limit damage from stressful stimuli and facilitate recovery.6 Acute and chronic exercise increases HSPs in intestinal cells where they can influence intestinal permeability, promoting cytoskeletal stabilization and preventing tight junction disruption.6
Every day it becomes easier for humans to survive than it was the day before, primarily due to technological advances. That is good for humans as a species, but only if humans also manage to maintain a balance of healthy stressors that keeps the hormesis cycles engaged and continues the tradition of positive adaptation.
- Peake, J.M., Markworth, J.F., Mosaka, K., Raastad, T., Wadley, G.D., Coffey, V.G. (2015). Modulating exercise-induced hormesis: Does less equal more? J Appl Physiol, 119:172.
- Gems, D., Partridge, L. (2008). Stress-response hormesis and aging: “that which does not kill us makes us strong”. Cell Metab, 7(3):200.
- Schirrmacher, V. (2021). Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications. Biomedicines, 9:293.
- Ji, L.L., Kang, C., Zhang, Y. (2016). Exercise-induced hormesis and skeletal muscle health. Free Radic Biol Med, 98:113.
- Pinches, J.L., Pinches, Y.L., Johnson, J.O., Haddad, N.C., Boueri, M.G., Oke, L.M., Haddad, G.E. (2022). Could “cellular exercise” be the missing ingredient in a healthy life? Diets, caloric restriction, and exercise-induced hormesis. Nutrition, 99-100:111629.
- Keirns, B.H., Koemel, N.A., Sciarrillo, C.M., Anderson, K.L., Emerson, S.R. (2020). Exercise and intestinal permeability: another form of exercise-induced hormesis? Am J Physiol Gastrointest Liver Physiol, 319:G512.
