The IL-6 Paradox: Highlighting the Complex Relationship between Exercise and Health

The complex relationship between exercise and health is both fascinating and intricate. It serves as a dual-edged sword, acting as a catalyst for disease prevention and treatment while simultaneously posing the risk of disease creation and progression.


Introduction

In the last decade, a transformative shift in our perception of muscles has unfolded, challenging the notion that their impact on well-being is limited merely to their mechanical action and increased blood circulation. This shift is encapsulated in the concept that ‘Exercise is Medicine’. Muscles, once seen as passive actors, now reveal their invaluable role in autocrine, paracrine, and endocrine signalling under specific circumstances, primarily through contractions. Despite this revelation, the deeper understanding of myokines, crucial signalling molecules exclusively released through muscle contraction, remains unfamiliar to many, including professionals in both exercise and medicine. [1][2] 

The physiological mechanisms set in motion during exercise have showcased their potential to enhance overall health conditions. The contemporary molecular comprehension of exercise's influence on health pathways, particularly its direct impact on inflammation and its interaction with the broader effects of whole-body exercise, carries significant implications for mitigating adverse health events. This understanding opens doors to the prospect of evolving treatment strategies rooted in a nuanced comprehension of the intricate relationship between exercise and disease progression.  [3]

While cancer takes centre stage in our discussion, given its widespread recognition as a foremost ailment, it's noteworthy that the implications extend beyond to general disease prevention. Recent discoveries add intrigue by defying traditional boundaries, exposing shared causal pathways among diseases typically perceived as distinct on the immune spectrum, including autoimmune diseases, obesity, and mental disorders. This revelation emphasizes the interconnected nature of diseases and underscores the need for a comprehensive understanding of the underlying mechanisms.


The IL-6 Paradox

One such physiological mechanism is the activation of Interleukin-6 (IL-6), a pivotal protein in immune system regulation, which paradoxically exhibits a dual role in either preventing or promoting cancer. It serves as a key biomarker in chronic inflammation development and stands as the primary indicator of the severity of various potentially life-threatening diseases. This has spurred substantial pharmaceutical research, particularly in the realm of biologics, where anti–IL-6 receptor monoclonal antibodies are employed as a specific remedy to inhibit the inflammatory impact, especially in severe cases of COVID. [4] 

Although it is produced in response to infections and tissue injuries, contributing to fevers in various diseases, its overexpression is observed in nearly all types of tumours. Elevated levels of serum IL-6, found in the bloodstream, are linked to the severity of COVID-19 and play a central role in the 'cytokine storm,' thereby influencing the risk of COVID mortality. Additionally, IL-6 is implicated in autoimmune conditions such as Fibromyalgia, showing significant connections to fatigue, functional status, sleep quality, and pain parameters. Its overexpression in blood serum is also a predictive factor for the risk or extent of heart and related diseases, disrupting insulin signalling and leading to type 2 diabetes. It influences platelet production and platelet activation, accelerating clotting and intravascular coagulation. Additionally, IL-6 is associated with various other conditions, including major depressive disorder, bipolar disorder and Parkinson’s disease.  Significant rises in IL-6 have also been observed with increased levels of stress and insomnia, and is predictive of therapy outcomes for Post Traumatic Stress Disorder (PTSD). It is also the primary indicator of ageing and age-related conditions such as Dementia, fertility issues, irritable bowel disease (IBD) and Crohn’s Disease, and as will be discussed in The Adiposity Connection, in obesity as well. [5][6][7],  [8][9][10]

Cancer patients with elevated levels of serum IL-6 and tumour necrosis factor alpha (TNF-α, an associated pro-inflammatory cytokine) was shown to have 6-times greater risk of mortality over the course of a medical follow-up. Elevated levels of IL-6 within the tumour microenvironment establish a strong correlation between inflammation and cancer. In this context, IL-6 fosters tumorigenesis by regulating key cancer hallmarks and shielding cancer cells from therapy-induced DNA damage, diminishing the effectiveness of anti-cancer drugs. [11][12][13][14][15]

However, IL-6 exhibits a dual role, functioning both as a pro-inflammatory cytokine (henceforth referred to as cIL-6) but also as an anti-inflammatory myokine (henceforth referred to as mIL-6). When triggered by the endocrine and immune systems to fight against disease or injury, it acts as a pro-inflammatory cytokine, promoting inflammation. In this state, it serves an initial immune protective purpose, but due to its volatility and non-specific function, it can potentially cause more harm than good, even becoming protective of cancer cells as previously mentioned.  Conversely, during exercise-induced muscle activation, it is expected to exert an anti-inflammatory effect, countering cytokines such as IL-6 (its cytokine counterpart) and TNF-α, an exclusively inflammatory cytokine. This occurs, however, only if muscle microtrauma is not induced, thereby initiating the mentioned external cytokine protective effect, namely, inflammation. [16]

Therefore, depending on the context, IL-6 can either prevent or promote cancer development. Released from skeletal muscles during exercise, IL-6 potentially enhances insulin sensitivity, stimulates anti-inflammatory myokines in the blood, and mobilizes protective effects against cancer. Conversely, sustained IL-6 signalling at sites of inflammation, such as microtrauma due to physical activity, through infectious diseases, and in the greater tumour microenvironment, promotes chronic low-grade inflammation and activates tumour-promoting pathways. [17][18][19]


Anti-Inflammatory Effect of Exercise

Aligned with the premise of the IL-6 Paradox, it has been observed that heightened levels of pain intensity associated with delayed onset muscle soreness (DOMS) correspond to increased levels of serum IL-6 24 hours post-exercise. In animal studies it was found that unconditioned mice had unrestrained muscle inflammation after treadmill activity, marked by the rapid accumulation of inflammation-promoting cells in their hind leg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality. This implies that exercise and activities inducing pain pathways might potentially contribute to an environment conducive to cancer development, particularly in individuals with compromised physiologies. This susceptibility may be evident in those with existing cancer, those recovering from chemotherapy, or individuals with a higher predisposition to cancer, such as those with excessive adiposity, as will be further elaborated in the next section. [20][21][61][62]

Conversely, a contrasting finding indicates that young, already highly conditioned individuals engaging in intermediate and reasonable exercises experience significantly decreased levels of both serum IL-6 and TNF-α immediately after the activity than before. This reduction therefore contributed to an overall decrease in inflammation levels than that measured before the activity, facilitating the healing and rapid recovery of muscles. It appears that the mechanism associated with the temporary elevation of IL-6 myokines, when not associated with muscle trauma that simultaneously releases TNF-α, results in the eventual decrease of both cytokines in the serum environment. IL-6 is generally higher during activity and can elevate up to 100-fold higher during exercise than the general background IL-6.  [22][23][24]

IL-6 release coupled with the release of TNF-α as a protective autoimmune response, may explain the IL-6 paradox. Though the exact physiological mechanism is linked to how the mIL-6 molecule combines with surface receptors during exercise, thereby limiting its beneficial reactions to in and around the actuating muscles. On the other hand, cIL-6 binds to a soluble version giving it a much longer shelf life and the ability to impact all cell types, driving inflammation and is the predominant pathway in disease formation, propagation, and perpetuation. Moreover, given that elevated cIL-6 is usually a response to injury, continues to persist for the duration of the damage, and is a key contributor to the development of chronic inflammation. And as mentioned in the 3rd paragraph of TheI L-6 Paradox, the prevalence of cIL-6 can be protective of cancer tumours, mitigating the efficacy of chemotherapies, and consequently a major potential impediment to cancer treatment and recovery. [25][26][27]  

Recent (November 2023) laboratory studies on animals sheds more light on the specific mechanism limiting the destructive impact of exercise induced inflammation. It suggests that individuals who are not accustomed to exercise may lack the necessary protective mechanisms against inflammation induced by physical activity. These unconditioned subjects also appear to experience considerable damage to their mitochondria. Notably, the typical proliferation of regulatory T-cells or Tregs that occurs with consistent and prolonged exposure to regular exercise, which serves as a protective factor against exercise-induced inflammation. Tregs are a subset of T-cells with a specialized role in regulating and suppressing immune responses to prevent excessive reactions that could lead to autoimmune diseases or chronic inflammation. This usually takes up to 6 weeks to develop sufficient protection with regular and progressively increased exercise, and does not appear to adequately develop in some cases thereby leaving cells indefinitely exposed to the effects of inflammationIn this regard, healthy functioning T-Cells can be a primary defence against cancer, and can potentially be significantly advanced by appropriate exercise, although exercise parameters like intensity, duration, and frequency need to be evaluated in more detail. [61][62]

In summary, acknowledging the IL-6 Paradox and understanding the substantial role of myokine IL-6 in potentially mitigating the impact of cancer through physical activity emphasizes the need for an exercise approach that fosters IL-6 myokine production without inducing secondary trauma linked to delayed onset muscle soreness (DOMS). Conversely, the latter is likely to heighten the risk of cancer proliferation due to prolonged increased levels of serum cIL-6 in the blood and the general area of trauma, with the potential to induce chronic inflammation, promote tumorigenesis and increase susceptibility to infection. The average unconditioned individual who has not developed adequate Treg responsiveness would likely have less of an ability to clear out inflammation through activity as the previously mentioned high conditioned athletes showed is possible. Thus, activating similar activity pathways to clear out inflammation is not that clear cut as a higher threshold for activating autoimmune responses could readily be triggered until a reasonable level of conditioning (in other words fitness) is achieved.       


The Adiposity Connection

Shared pathways between high adiposity and cancer have been identified, linking both conditions to low-grade inflammation. This inflammation is a prominent factor contributing not only to significant overweight but also to cancer formation. Individuals classified as highly overweight face an increased risk of developing various high-incidence cancers, with mortality risk rising relative to body fat percentage (BFP). [33][34][35][36][37][38][39]

This connection is notably associated with a dysfunction in the myokine activation of IL-6 in the context of high adiposity. This failure is implicated in both the development of high adiposity and also in cancer. The dysfunction suggests that the post-exercise repair process, particularly when causing muscle microtrauma, may be insufficient in clinically obese individuals, hindering their ability to regulate inflammation effectively. [40][41][42] 

This revelation underscores the crucial role of muscle activity in inflammation regulation, proposing that the post-exercise repair process may be insufficient, impacting its ability to control inflammation in both cancer and high adiposity. Exercise potentially induces substantial physiological changes in the immune system, akin to external stresses like surgery, trauma, or sepsis, eliciting hormonal and immunological responses. [43][44][45][46]

In simpler terms, microtrauma in muscles stimulates the production of protective hormones, such as the IL-6 cytokine and TNF-α, a cytokine released externally by the immune system to protect against perceived danger. Conversely, with optimal contraction without microtrauma, mIL-6, along with other beneficial hormones such as irisin, is produced internally by the sarcomeres through muscle contraction, functioning as productive anti-inflammatory myokines.

This observation establishes a link between cellular repair capacity, adiposity and the potential proliferation of cancer as a result of added trauma. In alignment with the Mitochondrial Dysfunction Theory of Cancer, elevation in inflammation levels potentially is a contributing factor to cellular and mitochondrial damage, and therefore the propensity for cancer proliferation. [47][48]


The Obesity Paradox

It's crucial to highlight that high adiposity encompasses more than just being overweight or obese; it generally includes individuals with low muscularity relative to the volume of adipose tissue, i.e., body-fat percentage (BFP). Consideration of the "Obesity (or BMI) Paradox" is important in this context, where many individuals classified as obese exhibit a higher likelihood of survival from various high-risk health conditions. What this suggests is, while obesity might put you at higher risk of getting cancer, it also puts you in a better position to recover from treating it.  [51][52][53][54] 

In this regard, obese individuals that are mobile would require a significantly greater muscle load to conduct normal activity. In other words, their significantly elevated weight disposes them to engage in a much higher level of Voluntary Intense Lifelike Physical Activity or VILPA than normal. This increased survivability, therefore, is directly linked to the degree of muscle mass, regardless of BMI. Additionally, low muscle mass coupled with relatively low fat (persons with very low BMI and reasonable to high BFP) significantly contribute to the risk of metabolic conditions. In this context, low muscle mass or poor muscle tone and function emerge as key indicators for the development of a host of diseases. In other words, lean muscle mass – the overall weight minus weight from body fat – is a better indicator of overall health, than either BMI or BFP. [55], [56], [57], [58], [59], [60]

An essential observation is that the protective effect of good functioning muscles is critical to health. Moreover, an exercise or therapeutic approach capable of fostering myokine signalling, as opposed to cytokine protective signalling created as an immune response, has the potential to reduce inflammation levels, mitigate chemotherapy resistance, alleviate sarcopenia (commonly known as cachexia in cancer patients), safeguard healthy cell mitochondria, and improve the overall fitness and functionality of individuals affected by cancer. Moreover, such a capability would prove beneficial for those dealing with weight-related issues in general, as well as associated diseases like diabetes, hypertension, in addition to cancer. 


Conclusion

The emerging understanding of myokines and their pivotal role in health, particularly in the context of exercise, presents a paradigm shift in how we perceive the relationship between physical activity and well-being. The IL-6 paradox, exemplified by its dual role as a pro-inflammatory cytokine and an anti-inflammatory myokine, underscores the complexity of these signalling molecules and their impact on disease progression.

The comprehensive exploration of myokines, the IL-6 paradox, and the adiposity connection underscores the significance of exercise as a potent tool in promoting health. The nuanced understanding of these molecular mechanisms opens avenues for tailored exercise interventions that can potentially reduce inflammation, enhance chemotherapy effectiveness, and improve overall fitness. As we continue to unravel the complexities of myokines, the integration of this knowledge into clinical practice holds promise for advancing preventive and therapeutic strategies for a range of health conditions.

The next chapter in this discussion is the protective role of Regulatory T-Cells or Tregs, in protecting cells against inflammation, but also how they can be protective of cancer cells against one's immune defences and chemotherapy. 

After successfully managing inflammation, the subsequent phase in the health equation involves exploring how the body can attain maximal mitochondrial oxidative capacity during exercise. This aspect is examined in "Lactate Metabolism in Health and Disease: The Interplay with ECS, Myokines, and Mitochondrial Oxidative Capacity." 

[Newton Fortuin, 7 January 2024]


Additional Notes on KineDek Use

Anti-Inflammatory Effect of Exercise

The following were observed from KineDek users’ experiences:

-   Sweating is generally not experienced during sessions although the body does warm up. This is indicative of the relative absence of fever type conditions akin to conditions of sepsis resulting from increased inflammatory cytokines, particularly IL-6, which usually is induced by conventional exercise.  [4][46] 

-  They generally report a feeling of lightness mentally and throughout their body. This is usually accompanied by increased mood and energy. [28][29]

-   Those with chronic pain conditions typically experience up to 5 days of remission of their pain. [30]

-  Those with hay fever and sinus conditions experience no or low incidence during the typical season.

-   Lower incidence of infections among weekly users. For instance, an individual who had battled stage 4 lymphoma, multiple myeloma, and bone cancer, who had completed chemotherapy just before starting Kinedek sessions, remained free from infections during the one-year period after initiating KineDek use. The haematologist overseeing the case noted that the person's body successfully resisted a potent respiratory strain in October 2023. Despite having had a lung infection, the individual exhibited no symptoms other than a mild fever. The haematologist, aware of the heightened risk of respiratory infections in the post-chemotherapy weakened state, remained especially vigilant during this period. He indicated that all his blood indicators were in the normal range.  [31] 

-   MD and physiologist Dr Margo de Kooker is a 100-mile runner who used the KineDek for three months. She reports that she has experienced roughly 80% improved recovery from muscle soreness (a day instead of 5 days) compared to her typical recovery time after an ultra-marathon event when doing a KineDek session a day before or on the day of the event. [32]

The aforementioned observations suggest that the use of KineDek leads to a reduction in the overall inflammatory profile of users for up to 5 days, particularly in the presence of an existing injury. Conversely, when there is no return of chronic inflammation, it suggests the absence of an underlying injury. The observed enhanced recovery in athletes in the days following use implies an improved protective resilience during this period. While it can only be speculated upon, the improved recovery after activity in both conditioned and unconditioned individuals and the reduced proneness to the severe effects of infection hints at a potential increase in muscle-residing Tregs activity, as will be discussed below, a major factor associated in improved outcomes for cancer. 


The Adiposisity Connection

Those who typically battle to lose weight consistently lose weight with KineDek use, without any observable dietary change. The once weekly 20-minute session alone in terms of energy expenditure, however, does not account for the reported weight loss. [49][50]

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