Exercise - Immune system connection
This is an introduction from research in the field of “Exercise Immunology”. Although many of these studies and research papers are not directly linking exercise and the immune system, many parts prove the connection and associated solution derived from the information. It should be noted that an investment of millions of dollars, time, very strict study guidelines, and human involvement would be needed to prove the same point. Many good studies can be used to understand how exercise influences the immune system like many other systems of the body. The nervous, digestive, endocrine, and skeletal systems are all intertwined and communicating with the immune system at many levels. Exercise is a physical stress stimulus that has manipulative capacities on the muscular system which makes it different than the other body systems.
Since there have been decades worth of evidence of fit populations and non-communicable diseases, it should be no surprise there is a link to communicable disease. Recently, solid research to uncover the mechanisms for the immune function and exercise created a new branch of science called “exercise immunology”. This new branch of study is the result of a broader understanding of both the muscular and the immune systems; how they communicate with each other and the other systems that overlap. The interesting aspect of this, which makes for an exciting discovery, is that the muscular system has such a powerful capacity to adapt and regenerate at amazing rates. Like no other organ, the muscular system can be stimulated by a variety of physical work forces. It can increase in size and efficiency and can be optimized in many ways. In a sense, if the muscle machinery of the body can be “upgraded”, so too can the other systems of the body. This likely makes “exercise immunology” one of the most important areas of research. Providing conclusive solutions that come from the information we currently have should be of no surprise.
First, just like any good detective, we begin by plotting some important points about how exercise is influencing the muscles and its effects are augmenting the immune system. Proven researched facts will corroborate these pieces, how they overlap and draw to this conclusion. From these points, some consensus can be drawn about what type of exercise is best to optimize immune function. A pragmatic approach would take into account of all the types of exercise while weighing the pros and cons of each of them. Beyond pragmatism and existing technology, a creative solution would take the best of what exercise has to offer and optimize the immune function by designing an exercise protocol. In many cases something that can be determined to be the best, but no one was really looking for it.
Understanding these points is the first part. Having a broad base of knowledge of exercise physiology and immune physiology is needed. As such, some basic information is provided as educational evidence from actual research to back up the claims. Some of these research papers are not directly looking at exercise-immune function, but can be used to point out other less-than-obvious conclusions from the data. Just because the scientific method is used to test a hypothesis from the data, it does not mean it did not uncover something else along the way. This is why reading the full text of research papers is important. When looking for clues that you are expecting to find do not reveal themselves, it does not mean other bits of data are not there. Sometimes it’s glaring in plain sight for someone else to see what is not being looked at or absent.
In the wake of the COVID-19 pandemic, we can make some broad stroke observations that the data has already shown. The biggest telling piece of data is the age of the subjects with the worst symptoms from the virus and the death rate in that particular population. They are older with compromised immune systems and in poor health. On the opposite end of that population spectrum are the lack of symptoms and death from the younger population. Viruses, bacteria, fungi, and other pathogens are can be indiscriminate, so the rate of infection should be the same. One could assume that the rate of transmission and infection is likely higher in the young population since they are less sanitary and interact at a much higher rate than the older population. In summary, older population equals intense symptoms and high death rate while younger population equals asymptomatic and very low death rate. This begs the question, “What are young people doing, or why are they different?” We will get to that as we have not yet seen any news coverage on the topic. Again, it’s not what you see, it is what you don’t see that holds clues.
One population that I am interested in during this COVID-19 situation is the population of people that exercises regularly. Especially interested in the higher aged population that exercises and what the COVID-19 reporting says. No data to my knowledge exists in tallying COVID-19 deaths from 65+ year old avid fitness participants. Of every main stream media death reporting the fine print has never revealed that “He worked out religiously, ate a nutritious diet, and did not take any prescription medications, and died from COVID-19”. We know for a fact that it is the exact opposite as death certificates say “COVID-19” to an older unhealthy population with pre-existing conditions. The COVID-19 deceased were exactly the opposite of the previously mentioned: older, fit, exerciser. They had non-communicable diseases, took prescription drugs to manage the disease, likely overweight, had a poor diet, and did not exercise.
So that is where the connection is from these first big points. It is a big association and to span those two points, it will take some dots of information in the middle to connect them. Below are some bullet points that will be used to fill in the dots and link exercise, muscle functions, and immune system functions, and performance. Many of the biggest connecting points are key concepts and terminologies.
Key Concepts and Terminologies
Exercise Immunology- a relatively new area of scientific endeavor; is the study of acute and chronic effects of various exercise workloads on the immune system and immunosurveillance against pathogens.
Immunosenescence- refers to the gradual deterioration of the immune system brought on by natural age advancement. The adaptive immune system is affected more than the innate immune system.
Immunosuppression - the partial or complete suppression of the immune response of an individual. Contributors are prescription drugs, malnutrition, cytomegalovirus (CMV) infection, alcoholism, diabetes, kidney failure, and other NCDs.
Mitochondria - membrane-bound cell organelles that generate most of the chemical energy needed to power the cell’s biochemical reactions.
Lactate - one of the substances produced by cells as the body turns food into energy (cell metabolism), with the highest level of production occurring in the muscles.
Myokines - one of several hundred cytokines or other small proteins and proteoglycan peptides that are produced and released by muscle cells in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.
Innate Immune Function - made up of barriers that aim to keep viruses, bacteria, parasites, and other foreign particles out of your body or limit their ability to spread and move throughout the body.
Adaptive Immune Function (also known as Acquired Immune System) - a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminates pathogens by preventing their growth.
Cortisol - a steroid hormone that regulates a wide range of processes throughout the body, including metabolism and the immune response. It also has a very important role in helping the body respond to stress.
Delayed Onset Muscle Soreness (DOMS) - pain and stiffness felt in muscles several hours to days after unaccustomed or strenuous exercise. The soreness is felt most strongly 24 to 72 hours after the exercise. Eccentric contractions are strongly correlated to produce the muscular micro trauma leading to DOMS.
HGH - a naturally occurring hormone produced by the pituitary gland. It’s important for growth, cell regeneration, and cell reproduction. HGH helps to maintain, build, and repair healthy tissue in the brain and other organs and systems.
Hormesis - any process in a cell or organism that exhibits a biphasic response to exposure of a substance, condition, or stress stimuli. The biphasic response can be positive to negative, or negative to positive after exposure.
OVERVIEW - Points to consider
- Populations with strong immune functions have low symptoms and can be somewhat asymptomatic and do not die from pathogens. If populations with strong immune functions could not protect themselves it is likely the whole human race would cease to exist from some previous pathogen. The strong survive, the weak do not.
- Aging populations are high risk and have a known decline in immune function which is called immunosenescence. Immunosenescence is also new field of study, and just like any cells of the body that age, they exhibit performance problems leading to senescence. Macrophages, NK cells, T-cells, B-cells, etc. have the same problem of declining performance.
- A main contributor to any cell line leading to senescence is thought to be “hypo-mitochondrial syndrome” which is the cells “powerhouse”, or mitochondria, cannot produce enough energy to keep up with repairs and removal of waste products. The build up of waste products are toxic to the mitochondria and further decrease power output of the mitochondria and is thought to be a major contributor to aging.
- Younger, fitter, exercising populations do not exhibit the traits of “hypo-mitochondrial syndrome”. Even older exercisers exhibit muscle components that are indistinguishable to younger variants and their mitochondria in the muscles do not seem to exhibit aging either. This syndrome is accelerated due to the lack of fitness, chronic toxin exposure, medications, stress, and reductions in Human Growth Hormone (HGH) and melatonin in the aging population.
- Exercise produces a substrate from muscle contractions called “lactic acid”, or under another term called “lactate”. The production of lactate stimulates the increase of size, performance, and replication of mitochondria. Lactate was once thought to be a waste by product of muscle contraction. Recently is has been discovered that it is a fuel substrate and a signaling product that stimulates Leydig cells to produce testosterone which one of the most powerful anabolic androgenic hormones.
- If exercise is of adequate intensity (harder muscle contraction forces), lactate is evacuated from the muscle cells and is distributed to other types of cells in the body via the circulatory system. This lactate is then used by other cells of other body systems as a fuel source with the same stimulating effect to the mitochondria of those systems to increase size, performance, and replication of those mitochondria.
- Immune cells become part of this “up regulation” from exercise induced lactate and thus become resistant to immunosenescence via increased mitochondrial function and other signaling molecules. If one is already immunosenescent, exercise has been shown to reverse this by several proposed signaling mechanisms and frequent lactate exposure that leads to increased mitochondrial performance likely plays a key role.
- Innate and adaptive immune functions are also modulated by “myokines” which are cytokines by classification. These myokines are named because skeletal muscle cells (myocytes) are producing them at rest and during contractions. These myokines are just recently discovered and some that have been identified show direct signaling pathways from contracting skeletal muscle to the immune functions.
- The myokine interleukin-15 (IL-15) is a pleiotropic cytokine with a broad range of biological functions in many diverse cell types. It plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites by modulating immune cells of both the innate and adaptive immune systems. It is one of the many muscle producing myokines that signal-modulate the immune system.
- Cytokines are a complex group of signaling proteins from every cell type and systems, and are used to communicate with each other. There are an estimated 600+ myokines, which are a subclass of cytokines, that the skeletal muscle system uses to communicate with other organs and systems. Since the muscular system is by far the most abundant tissue in the body and secretes and receives communication signals, it is now considered an organ. It has a functioning communication system that has autocrine (self signaling), paracrine (near vicinity signaling), and endocrine (full body system signaling) pathways.
- It is well documented that exercise increases immune function and performance if exercise is performed with moderate intensities and frequencies. The innate immune function is enhanced, and the adaptive function is also enhanced depending on what type, intensity, and frequency of the exercise. The combination of these factors for exercise and immune function are thought to be specific to performance types.
- However, due to a negative to positive hormesis effect, high intensities and frequencies of extreme exercise protocols can cause a temporary suppression of the immune system functions. This “immunosuppression”, is a result of the release of cortisol and the immune functions being redirected to aid in recovery from the physical stress of the exercise bout. High intensity exercise does create more lactate, which is great, but at the cost of an increase in cortisol, damaged tissues that need to be repaired, and the a weakened immune system during this process.
- Oxidative stress and mechanical stresses create an enormous amount of cellular damage and the release of cortisol to produce inflammation is a result as it is a part of the healing process. Cortisol is immunosuppressive acutely and chronically.
- High amounts of aerobic exercise causes immunosuppression that leads to upper respiratory tract infections as a result of the lungs being overwhelmed from excessive air inhaled that leads to increased particulate inhaled. Aerobic training also does not increase the anabolic hormones like resistance training does, and at extreme levels can actually be “catabolic”. Anabolic hormone up-regulation is needed to counteract the catabolic effect from cortisol, or blunt some of the effects, which is likely needed to increase immune cell replication and renewal.
- High intensities of resistance training causes high amounts of anabolic hormones, but there comes a cost if done with weights as the negative phase of the hormetic effect is greater. Weights create a higher amount of cellular damage in the muscle from eccentric contractions as result of physics and how a repetition is performed. Delayed Onset Muscle Soreness (DOMS) has been clearly associated and established that the eccentric phase of the muscle contraction leads to cortisol production. DOMS can last over 72 hours, and if repeated bouts overlap recovery the condition is chronic.
- As we age this negative portion of the hormetic response increases from declining HGH and testosterone. The reduction in anabolic signaling to recover from stress as we age increases the window of immunosuppression and is likely to accelerate immunosenesence.
- As eccentric contractions are creating muscular damage that leads to extended periods of DOMS, cortisol is also elevated during this time. This elevated cortisol is creating acute and chronic periods of immunosuppression. It has been well studied how other types of non-physical stresses increase levels of cortisol and this condition is called “hypercortisolemia”, which is a chronic elevated cortisol condition. Immunosuppression and premature immunosenescence are just some of key conditions and symptoms of hypercortisolemia.
- Interestingly, research shows the concentric phase (shortening of the muscle under load) of the contraction creates more lactate compared to eccentric contraction (lengthening under load) phase and is not associated with DOMS. This concentric part of the repetition does not create the magnitude of damage that the eccentric contraction portion does since the contractile fibers are not being mechanically pulled apart during contraction during eccentric contraction. Certain types of exercise programs, styles, and recently products are focusing on concentric contraction activities to mitigate the negative aspects of exercise and boost the positive attributes.
What does this mean?
Connecting the dots from performing exercise that optimizes immune function can now be linked by understanding that muscle and the contractions that provide forces also produce unseen communication to all systems. Exercise is also influencing other systems that influence the immune system as well. The muscular system has direct and indirect modulation capacities and these communication pathways are not one-way paths. The complexity of this inter-system is far beyond the scope of this review. Understanding the mechanisms of the mentioned subsystems sheds light on how this is not just a mere association, but now can be objectively identifies and measured.
To be clear, exercise does not cure COVID-19, or any virus, just as vaccines do not either. The immune system and its cellular arsenal do the curing. It must be clearly understood that the immune system does the killing of the virus and assists the healing of the body. The bottom line is the body heals itself. A healthy person can neutralize a virus infection and eradicate itself of the virus. A fit person that optimizes human functions via exercise is far more capable of dealing with a virus. An analogy is a gun and bullets. A gun cannot do anything without bullets since the gun provides the mechanism for the bullet to hit the target. To hit the target you need sights that identify the target. Exercise provides more powerful bullets and an accurate targeting system for the immune system to identify the pathogen.
Fitness, which is an elevated state of metabolism, cannot be attained through any mechanism (diet, supplement, drug, etc.) other than exercise. Fitness is another level beyond being healthy and there are many levels of fitness. Since there is a strong correlation of the skeletal muscle system doing the work during exercise and the whole physiology of the individual becoming increasingly robust, it should be no surprise that a fit individual has a fit immune system that is potentially higher performance than a normal one.
With existing strong evidence from research to support exercise as the number one treatment for non-communicable diseases such as cardiovascular disease, diabetes, cerebrovascular disease, cancer, obesity, etc., should it be any wonder that exercise would also be the treatment for communicable diseases as well? If the immune functions are optimized in performance from exercise, or operating efficiently like that of young adult or athlete, this would be a convincing reason why the data supports specific young and fit populations are low risk and the opposite high risk are being extremely symptomatic or dying from COVID-19.
This information has been accumulating for over a century, and in the last 20 years alone there have been over 100+ studies directly showing the benefits of exercise immunology and the underlying mechanisms that makes it an undisputable correlation. This begs a serious question or two about our health professionals and organizations that the media continually covers regarding the pandemic. Since these professionals and organizations are the ones that peer review all of this research and the conclusive findings, why aren’t they mentioning how exercise immunology can enhance the immune system and save lives? They either do know about exercise immunology and all the benefits, or they don’t. If they do know, why haven’t they mentioned it since it is glaringly apparent from the population data. If they don’t know about exercise immunology and the benefits, then maybe they aren’t experts.
Exercise Prescription for Immune Optimization
Exercise is a broad term and there are many different types of exercise depending on what type of fitness characteristics one wishes to attain. Exercise styles, programs, protocols, and activities all have their areas of emphasis. All seem to act on an adaptive hormetic response to resistance. Resistance is the stress that your muscles work against and resistance types produce different adaptive effects. If one were intrigued enough to evaluate specific resistance properties that create specific adaptive qualities, the most optimum exercise prescription can be designed. Or you could just do a bunch of different activities to cover all the bases and hope for the best. It’s a shotgun or grenade approach to getting it done, while a laser sighted rifle would have worked much better and efficiently. In this case, the aim is to optimize the immune function without sacrificing anything.
As new research about exercise physiology replaces gym dogma, training science reveals the true mechanisms of muscle and training stimulus. The discovery that concentric contractions create higher amounts of lactate that signal testosterone production and eccentric contractions being responsible for DOMS and cortisol was of big interest. It had always been thought that you had to create muscle soreness to grow. And now research is finding that lactate production and from muscle contractions and this create most of the anabolic signaling effects to increase contractile fibers and mitochondria. This systemic effect diffuses throughout the body causing non-exercising cells to increase in mitochondrial fitness as well. The discovery of myokines produced by contracting skeletal muscle that communicate with the rest of body also has increased the value of exercise tremendously and shaped the exercise protocols.
The perfect exercise prescription for a “high performance immune system” would take into account many of the points found in this full report. You would want an exercise protocol that would increase mitochondrial functions outside of the muscles from high amounts of lactate production from the muscles. You would select an exercise protocol that activates all types of muscle fibers that produce larger pools and types of the different myokines. One would also look to a type of exercise that increases HGH/IGF-1 as well. Resistance training is the obvious choice for mitochondria genesis, increasing HGH/IGF-1, and myokine signaling. Not to mention resistance training makes your muscles bigger which increases other metabolic situations that assist your immune system. Seems like resistance training is the way to go, right? It is, but not so fast, it could be better yet with some tuning adjustments.
The downside of resistance training is that it is mostly done by lifting-lowering weights in a cyclic fashion. This is standard and performing weight training in this fashion and is linked to immunosuppression. One of the previously mentioned points is that “eccentric contractions are responsible for DOMS and cortisol” and another point was cortisol is well known to be immunosuppressive. DOMS does not occur every time you train with weights, and in fact if done with regular frequency DOMS is reduced. But that is not true about the cortisol. Cortisol does not create DOMS. It is present whether you feel sore or not. Just because muscle CAN lower weights with an eccentric contraction does not mean we are supposed to do it repetitively. Muscles were meant to do work with concentric contractions 99% of the time. Lift/lower repetition cycling for muscular development is not normal. “Tearing down the muscle to rebuild it bigger” is not normal and it is unnecessary as it reduces satellite muscle stem cells prematurely.
This solves the problem of resistance training with weights being immunosuppressive. The conclusion is that resistance training in short intense bouts with regular frequency with specialized equipment using nitrogen gas pressure is the optimal protocol for high performance exercise immunology. All the great benefits of resistance training without the downside of elevated cortisol and being sore all the time. “Less Pain-More Gain” should be of interest to anyone, especially those who are looking to increase their health and fitness. For those older populations this is great news as it now has a benefits they desperately need in optimizing an Anti-Aging strategy to extend their health span by optimizing their immune system capacity.
Potentially exercise immunology and providing an optimum solution is one of the most important breakthroughs in today’s pandemic climate. In addition to some simple nutritional components to add to the mix to make it even more potent, no person should ever fear something like what is happening now. Educated, armed, and prepared. It has been stated in many well regarded publications that “exercise is the best medicine” and now that statement is has more weight. The human physiology has a remarkable capacity to heal itself and understanding the mechanisms behind that is where medicine should explore. Understanding a problem and then coming up with solutions, then testing them to see what is the best solution gives us our unique absolute superiority as a species.
The COVID-19 virus and future viruses to come will challenge our human species and it always seems that we bank on the development of vaccines to save us when a crisis hits. The optimization of the immune functions should be the preparation and we should be ready all the time. The use of vaccines are actually tested on subjects with healthy robust immune systems. So what does that tell you? If you are unhealthy, immunosuppressed, you are not supposed to be vaccinated as it is a risk for complications. Instead of waiting for the next pathogen to come upon us and wait for an antidote we should be arming ourselves with a “bullet proof” immune system. Because if an optimized immune system can’t defeat a pathogen, then it is unlikely that a vaccine will. 12-18 months for scientists to learn how to make a vaccine which the immune system can then make antibodies from and possibly produce immunity is the pharmaceutical route. It may work, it may not. Or, actually get the virus, let a fit innate immune system take care of it and the adaptive immune functions make antibodies from it and become immune for life. You have two choices. Give someone else control, or you can be in control. Information is great, but solutions are the key. Knowledge is power and putting knowledge to work is powerful!
(1) Mitochondrial Dysfunction and the Aging Immune System
by Peter J. McGuire
Metabolism, Infection and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
Biology 2019, 8(2), 26; https://doi.org/10.3390/biology8020026
Received: 9 November 2018 / Revised: 4 January 2019 / Accepted: 16 January 2019 / Published: 11 May 2019
(2) Eccentric Muscle Contractions: Risks and Benefits
Stéphanie Hody,1,* Jean-Louis Croisier,1 Thierry Bury,1 Bernard Rogister,2,3,4 and Pierre Leprince2,4
Front Physiol. 2019; 10: 536.
Published online 2019 May 3. doi: 10.3389/fphys.2019.00536
(3) Muscles and their myokines
Bente Klarlund Pedersen
Journal of Experimental Biology 2011 214: 337-346; doi: 10.1242/jeb.048074
(4) Stimulatory effect of lactate on testosterone production by rat Leydig cells.
Lin H1, Wang SW, Wang RY, Wang PS. J Cell Biochem. 2001 Jun 26-Jul 25;83(1):147-54.
(5) The ins and outs of muscle stem cell aging
Andrew S. Brack & Pura Muñoz-Cánoves
Skeletal Muscle volume 6, Article number: 1 (2015)
(6) Exercise-induced myokines in health and metabolic diseases
Integr Med Res. 2014 Dec; 3(4): 172–179.
Published online 2014 Oct 5. doi: 10.1016/j.imr.2014.09.007
Byunghun So,a Hee-Jae Kim,a Jinsoo Kim,a and Wook Songa,b,⁎
(7) Exercise immunology: practical applications.
Int J Sports Med. 1997 Mar;18 Suppl 1:S91-100.
(8) Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects.
Exerc Immunol Rev. 2015;21:8-25.
Peake JM1, Della Gatta P2, Suzuki K3, Nieman DC4.
(9) Interleukin-15 improves cytotoxicity of natural killer cells via up-regulating NKG2D and cytotoxic effector molecule expression as well as STAT1 and ERK1/2 phosphorylation.
Cytokine. 2008 Apr;42(1):128-36. doi: 10.1016/j.cyto.2008.01.003. Epub 2008 Feb 15.
Zhang C1, Zhang J, Niu J, Zhang J, Tian Z.
(10) IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells
Published online 2016 Sep 21. doi: 10.1155/2016/5465804
Shantaé M. Thornton, 1 James E. Krolopp, 1 and Marcia J. Abbott 1 , 2 , *
(11) The Somatotrope Growth Hormone-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor-1 Axis in Immunoregulation and Immunosenescence.
Front Horm Res. 2017;48:147-159. doi: 10.1159/000452913. Epub 2017 Feb 28.
Bodart G, Farhat K, Charlet-Renard C, Salvatori R, Geenen V, Martens H.
(12) Eccentric Muscle Contractions: Risks and Benefits
Front Physiol. 2019; 10: 536.
Published online 2019 May 3. doi: 10.3389/fphys.2019.00536
Stéphanie Hody,1,* Jean-Louis Croisier,1 Thierry Bury,1 Bernard Rogister,2,3,4 and Pierre Leprince2,4