Hormetic Exercise Promotes Human Health and Resilience

Introduction

Resilience and health have become two interchangeable words with adaptation to environments being at the root of both. Physical fitness provides a mechanistic means of adapting to a variety of environments and biological stresses. While physical fitness does not have to be painful, there is a level that must be reached in order to reap the myriad of health and resilience benefits that can occur in endogenous physiological systems, and biochemical pathways. This involves a progressive hormetic approach[1]of partaking in the biological stress and physical discomforts of high-intensity exercise. The aim of this paper is to not only provide a case for hormetic exercise protocols for multiple areas of further health research and promotion, but the aim is also to provide contexts where this type of training can be helpful while also being cognizant that even hormetic exercise needs to be monitored and managed to prevent any form of overtraining residual such as high reactive oxygen species production. A holistic approach (the holistic effect[2]) of the biochemical and physiological effects of high-intensity exercise (cardiorespiratory and/or resistance training methods) versus low and moderate-intensity exercise and its protective factors on health will be provided. 

A Case for More Stress in Promoting Health

It has long been debated that actions and behaviors of human nature are driven by a seeking of hedonic experiences, and an avoidance of discomforts and pain. This often-cited opioid and dopaminergic way of living just may be why the morbidity and mortality rates related to lifestyle factors continue to rise, and these behaviors are why a push for primary prevention in health care resource allocation for behavioral education should include the benefits of hormesis through exercise. ^{1 2 3} It is well-established that exercise upregulates stressful biochemical processes and their opposing responses, which facilitate beneficial phenotypic health parameters.⁴ The association between health and resilience from the physiological conditioning and adaptation of challenging exercise and its ability to epigenetically change mechanisms in humans if the means to do so are enforced and supported. ^{5 6}

See appendix for a sample week of a hormetic exercise protocol.

Anaerobic Metabolites as Moderators of Poor Health

            Today it is unequivocally evident that exercise can produce some level of health-promoting biomarkers in most populations with specific attention to typical age-related conditions such as cognitive decline and cardiometabolic diseases. The question within this statement is what type of exercise can be used to promote health and higher quality of life for the majority at the quickest rate while setting us up for success as we age. Mounting evidence supports that high-intensity exercise at an approximate 90% VO² max or 85-100% maximum heart rate (hormetic exercise or HE) provides this solution. ^{29 30} HE relies heavily on the end product of the glycolytic pathway, pyruvate. Pyruvate produced in the payoff-phase of glycolysis when under hypoxic conditions, undergoes fermentation primarily by the enzyme lactate dehydrogenase to lactate. This metabolite has been shown to increase neurogenesis in the adult brain⁷, an important aspect of retaining cognitive functioning like memory as we get older. Lactate produced through HE is also one of the few substrates that can supply energy across the blood-brain barrier via monocarboxylate transporters (MCT) and can also aid in cognitive functioning as an energy substrate for the brain when glucose availability is low. Another major finding of this promising and interesting work is Kelch-like ECH-associated protein 1 (KEAP1). Given the relationship between keap1, redox status, and the vitagene network, there is a possible biological relevance in neuroprotection in that this particular protein can be activated during high-intensity hypoxic and ischemic exercise like HE, upregulating essential antioxidants like catalase.^{32 33 34}

Creating cellular anaerobic environments within the muscle cells and biochemical pathways of the body through short bursts of supramaximal (120% VO_2max) exhaustive HE over longer duration moderate or light intensity training, also provide greater activation of GLUT4 glucose transporters and fatty acid transporters, both of which are key moderators of cardiometabolic conditions such as diabetes and heart disease by aiding in the shuttling of excess glucose and fats in the blood to the working muscle tissue for the energy use of glycogen repletion.⁸ HE requires a more rapid and elevated energy demand than its antagonist form of training which means results in a significant increase in AMPK activity. This increase in AMPK activity also provides means for the use of glucose and fatty acids over storage and accumulation of lipoproteins in the blood and on cell walls.

Sarcopenia is another issue that comes with aging that affects the aforementioned health conditions while also increasing the potential for additional comorbidities related to loss of muscle function. It is also of importance to mention that cellular health through physical training of a high intensity also increases 3-β-hydroxybutyrate which promotes the expression of brain-derived neurotrophic factor (BDNF) to support dendritic spines and neurophysiological communication⁹. Mitochondria biogenesis and bioenergetics are vastly important for our all of our cell’s survival¹⁰. DNA methylation plays an integral role in these facets and researchers have shown that exercise increases cell sensitivity and functionality with mRNA promoting PGC-1a, mitochondrial transcription factor A, PPAR, and pyruvate dehydrogenase kinase isoenzyme 4, all of which are necessary for muscle cell survival and function.¹¹

The Redox System’s Effect on Health Outcomes

As was previously stated, HE requires short bursts of activity over longer duration exercise with the length of the overall activity (>60mins) being paramount.³¹ This time factor of exercise-specific energy system demand is crucial as metabolic byproduct production and waste regulation occur at a faster rate in hypoxic exercise that of which can only be sustained for short periods¹⁵. With HE there is a need for greater aggregation of metabolic substrates and metabolites to drive physical output. This means a large trigger of anaerobic enzymatic and non-enzymatic mechanisms to initiate and carry out the exercise followed by a greater influx and super-compensation of our endogenous antioxidant systems post-activity to replenish what was lost. While Souza et al.¹² did show that aerobic exercise had some positive effects on the redox system, the larger influx of antioxidants that comes from HE in addition to the additional activation of the lesser recognized protective xanthine oxidase was only shown in hypoxia-inducing exercise. The fine balance between deleterious effects of excess ROS generation such as a misfolding of proteins, apoptosis, autophagy, or mitophagy pathway activation has the potential to be controlled through mechanisms of HE through an antioxidant multiplicity of superoxide dismutase and glutathione which encourage allosteric binding on sites for cell health.

To further elucidate the importance of the exercise-induced management of reactive oxygen species, ROS handling, and redox signaling are also elevated more efficiently through HE to counteract deleterious effects of lipid peroxidation and carbonylation of amino acid residues¹³. These factors have been associated with health outcomes related to cancer progression by means of imbalanced production versus use or elimination of mitochondrial respiratory byproducts such as superoxide anions (O₂ ^−•), hydroxyl radicals (^•OH), nitric oxide (NO), and other species such as hydrogen peroxide (H₂O₂), singlet oxygen with the OH being the most reactive¹⁴. In aerobic metabolism or oxidative phosphorylation, there is a constant of uncoupling reactions that occur for to regeneration of ATP. These uncouplings produce the reactive species that leave cells vulnerable to the binding of the above-mentioned ions. It is of interest to point out that endogenous SOD2 levels (the antagonist to the superoxide anion radicals) only increased when exercise was part of a weekly schedule¹⁵ with SOD2 being an important antioxidant enzyme against oxidative damage relating to deleterious health issues¹⁶.

Hormetic Exercise for Pain Modulation

Within humans is a capacity to modulate our reaction to pain through our opioid/β-endorphin, and the endocannabinoid system. It can even be learned that a certain level of discomfort can provide a positive outcome if efforts are made in addressing psychobiological aspects of pain moderation. This could include a reframing of what the discomfort means ie. the discomfort being felt during exercise is not a threat, but a means to an end of becoming stronger and healthier. In doing psychological work, it could be possible to truly reap the benefits of hormetic exercise training.

Pain is now only mildly seen as being related to tissue damage and this is often only acute pain. Chronic pain is a more serious problem with its basis being implicated at a neurobiological (nociception and neuropathic) level, and exercise continuously being proven to be a solution for both. More specifically, it has been shown that high-intensity exercise has the greatest analgesic effect through mechanisms activating the endocannabinoids N-arachidonoylglycerol and 2-arachidonoylglycerols both of which act on a receptor that alters emotional and cognitive responses relating to pain¹⁷. The PPAR family of nuclear receptors are also involved in pain modulation through BDNF signaling. During times of increased demand for energy with reduced access to ATP, AMPK levels can rise and the PPAR family of nuclear receptors become activated. This process occurs at a faster rate during HE as signaling for physical work output surpasses the ability of the human systems to replenish fast enough endogenously.

Heyman et al.¹⁸ showed that metabolites for endocannabinoids, β-endorphins, and BDNF levels only all increased when a maximal exercise test was performed. BDNF works on the pain pathways by controlling glutamatergic and GABAergic activity¹⁹. Glutamate decarboxylation and an increase in GABA receptor function occur which facilitates BDNF and a calming effect on the nervous system. This action is driven through exercise²⁰ while negative stress responses that can come from the excitatory neurotransmitter glutamate being hyperresponsive, are moderated by exercise by depolarization in glutamatergic synapses α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These AMPA receptors are fast ligand-gated cation channels that are dependent on an influx of Ca2+ ²¹, but this influx is bypassed by the need for this element for myocyte function in exercise.

CONCLUSION

Exercise of various types all have the means to help us be more resilient but it is the type, duration, and intensity dose-response that proves to be of utmost importance. It is evident that physical training has protective effects across multiple health outcomes, but it continues to become clear that the effort we put into exercise training will reward us accordingly. Progressive high-intensity hermetic exercise > 60 minutes of duration, involving short bursts of high output of heart rate and VO₂ max responses ie. sprints, heavy lifting, or interval of ergometers, proves to be the most time-efficient modality to prevent and even treat some disease occurrences and progressions. In promoting HE as a more valuable method of exercise over long-duration low-to-moderate exercise, compliance may be heightened as time is often a factor in people not engaging in weekly exercise.

From a population standpoint, there is still a long way to go in terms of exercise prescription as it truly is very personal medicine, but the potential rapid biological and physiological responses over other modes of exercise should not be ignored. Hormetic high-intensity exercise is only just starting to reach the necessary populations as a means of a higher quality of life using an approach of embracing the discomfort versus relying on simpler exercise modalities as is the way of the past. Evidence of molecular mechanisms to prevent senescence with hormetic exercise continues to mount and it is important to be used in conjunction with other physical activity promotion for optimal maintenance of independence and disease prevention.

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Appendix

[1] Hormesis refers to “a process in which a low-dose of a chemical agent or environmental factor that is damaging at high doses induces an adaptive beneficial effect on the cell or organism” (Mattson MP. Hormesis defined. Ageing Res Rev 7: 1–7, 2008). In the case of address in this review paper, the agent of stress is high-intensity physical exercise and the physiological and biochemical responses that arise from its performance.

[2]A holistic effect means that multiple functional human systems are being considered and affected. A holistic approach does not compartmentalize nor does it disregard the importance of the external environment and its effect on the host.