Hormetic Exercise Promotes Human Health and Resilience
I will warn (?!?) you in advance that this is not a typical blog post of mine but as I keep streamlining, you will get these on occasion when you might be expecting something more actionable and digestible for general health, fitness, and well-being. I do still hope you enjoy and find motivation in the review of how hormetic exercise promotes human health and resilience.
Hormetic Exercise Promotes Human Health and Resilience
Resilience and health have become two interchangeable words with adaptation being at the root of both. It has long been debated that actions and behaviours 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 global rate of obesity and its related comorbidities continue to rise (C.D.C., 2020; Yohn et al., n.d.; Leknes & Tracey, 2008) and why a push for healthcare and prevention to include hormesis through exercise as a mandatory policy. It is well-established that exercise upregulates stressful biochemical processes and their antagonistic responses which facilitate beneficial phenotypic health parameters (Margaritelis et al., 2020). There is a correlation between health and resilience that comes from the “conditioning” and “adaptation” (Peake et al., 2015) of challenging exercise that can epigenetically change (Simmons, 2008) us if the means to do so are enforced and supported. While physical fitness does not have to be “painful” there is a level that must be reached in order to reap the myriad of benefits to all endogenous systems. This involves a progressive hormetic approach of “leaning into” the biological stress and physical discomforts of high-intensity exercise and resisting our nature’s calling. 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 regardless of demographic but to provide contexts where this type of training can be helpful. A focus on different health systems from a holistic approach (the holistic effect), and 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
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 like 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 (hormetic exercise or HE) provides this solution. 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 brain (Lev-Vachnish et al., 2019), 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).
Creating an overall anaerobic environment within the body through short bursts of supramaximal (120% VO2max) 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 like diabetes and heart disease (Torma et al., 2019). 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 the 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 communication (Leak et al., 2018). Mitochondrial biogenesis and bioenergetics are vastly important for our all of our cell’s survival (Nelson & Cox, 2017). DNA methylation plays an integral role in these facets and Vitosevic et al. (2019) 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.
The Redox System’s Effect on Health Outcomes
The regulation of oxidative stress and antioxidant production has proven to be a key parameter in overall human health. Oxidative stress and its byproducts reactive oxygen species (ROS) have been demonized as a source of human demise for years, but these molecules are actually essential to our survival if managed accordingly. As was previously stated, HE requires shorter bursts of activity over longer duration exercise. This time factor is crucial as the energy systems work quite differently under certain time frames. This ticking clock also holds a window open for metabolic byproduct production and waste regulation that has been shown to occur at a faster rate in hypoxic exercise that can only be sustained for short periods. 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. (2019) 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 the deleterious effects of lipid peroxidation and carbonylation of amino acid residues (Radak, 2017). These factors have been associated with 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 reactive (Barrera, 2012). 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 binding of the above-mentioned ions. When you prioritize exercise that primarily uses oxidative phosphorylation pathways for extended for long durations, you increase your time and overall volume of exposure to ROS versus using HE that does not rely on the same mechanisms and rates of substrate utilization and repletion rates. 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 schedule (Hyatt et al., 2015) with SOD2 being an important antioxidant enzyme against oxidative damage relating to cancer (Aggarwal et al., 2019).
Hormetic Exercise for Pain Modulation
Within each of us is a capacity to modulate our reaction to pain through our opioid/β-endorphin, and the endocannabinoid system. In fact, we can even learn to enjoy a certain level of “pain” if we keep working at it and thus, be able 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 from multiple lenses 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 pain (Gorzalka & Hill, 2011). 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. (2012) 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 activity (Merighi et al., 2008). 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 exercise (Ferreira-Junior et al., 2019) 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+ (Leem, 2017), but this influx is bypassed by the need for this element for myocyte function in exercise.
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 exercise that creates a hormetic stress response proves to be the most time-efficient modality to prevent and even treat some disease occurrences and progressions. From a population standpoint, there is still a long way to go in terms of exercise prescription as it truly is very personalized medicine. Hormetic high-intensity exercise is only just starting to reach the necessary populations as a means of a higher quality of life and while molecular mechanisms can be helpful in further corroborating HE as an essential to life, the real questions and supports need to focus on the how-to of getting all stakeholders on board and doing what’s needed on a weekly basis to prevent senescence as long as possible while maintaining independence and enjoyment for the elongated duration.
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 “Hormesis is a term…to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress” (Mattson, 2008). In this case, the agent is challenging physical exercise.
 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.