FATIGUE, PAIN, AND HOW THEY RELATE TO AGING

Throughout my thirty-eight years of medical practice, most patient visits involve complaints of either fatigue, pain or both. I have come to understand that they are inextricably linked by how inflammation works. Pain can cause or effect fatigue and fatigue is often linked to all types of chronic pain. Because these symptoms are so encompassing and often require different levels of urgency to diagnose and treat, the root cause(s) are easily overlooked. Far too often, the diagnosis is whitewashed in disease treatment and reduced to band aid approaches involving addictive painkillers, antianxiety medications, antidepressants, sleeping pills, muscle relaxants, or combinations of some or all of them. Often imaging and surgery are recommended but fail to control symptoms after periods of time.

While these treatments are well intentioned and offer some semblance of symptom relief, the long-term consequences of drug addiction and brain fog from untoward and addictive side effects nag a productive life. The choice is often to live with debilitating fatigue and pain, or accept the side effects, and brain fog from painkillers, antianxiety and sleeping pills. The fact is simple, all the drugs used to ameliorate pain and fatigue produce their own set of problems that can be just as bad over time as the pain and fatigue. The basis for this fact is that these medications often only relieve symptoms, can be very addictive, have their own sets of side effects and tend to lose their effectiveness over time. Remarkably they do not address the chronic inflammatory root cause(s) of pain and fatigue.

With the passage of time, as tolerance to treatments increases, even more addictive medication is required to alleviate symptoms. This creates an unrelenting spiral of potentially adverse outcomes that leave patients with even less capacity to function. Normal living gets reduced to basic subsistence and dependency upon addictive drugs. Depression, disability and suicide can be just around the corner.

Identifying the root cause is notjust about which end organ is involved in the pain and fatigue complex. Although one end organ appears to be causing symptoms, there are usually underlying inflammatory conditions that are affecting all end organs. The inflammatory condition thus becomes a root cause. For example, chronic low back pain is often associated with a protruding intervertebral disc, or arthritis in joint spaces that affects nerve roots. What becomes perplexing in the treatment of low back pain is that predictability of who has the most pain based on imaging of the back is a crap shoot. Some patients have no back pain with horrific x-rays while others have severe back pain with very little evidence of arthritis. In other words, there is often no correlation between back pain and abnormalities seen on imaging. Could the difference be tied to the presence or absence of chronic inflammation?

I would suggest that any end organ pain or fatigue increases or decreases based on the presence or absence of chronic inflammation. Mitigating chronic inflammation, as root cause, has a significant impact on all types of different end organ pain or fatigue. While it is reasonable to focus resources on urgently alleviating disabling pain, the inflammatory elephant in the room should not be ignored. Identifying the root cause(s) of inflammatory pain and fatigue therefore takes on a more holistic understanding of health, as it biases discussion about anti-inflammatory lifestyles. When implemented, pain and fatigue often remit regardless of which end organ these symptoms appear to originate from. In the context of lifestyle and prevention, evaluating pain and fatigue takes on a different narrative, as reversing inflammation becomes a top priority.

In the case involving low back pain, this would mean mitigating inflammatory risks. Besides reducing dietary sugars, cigarettes, and stress, behavioral prevention programs involving low back stretching, sleep positons, as well as utilizing proper techniques in bending and lifting in aggregate substantially improve low back pain. As important as these behaviors are to addressing root cause, the fall out is that the back pain has a far greater likelihood of decreasing without relying on drugs or surgery. When lifestyle management causes a regression in pain or fatigue, patients gain greater confidence in managing their health which reinforces more wellness while making them less vulnerable to addicting narcotics or sleeping pills.

Reducing inflammation by reducing vascular inflammatory free radicals allows not only low back pain to improve but cascades occult improvements in other end organs. In the holistic, root-cause approach, the low back pain becomes the red flag to underlying inflammation that needs to be addressed with lifestyle adjustments. Doing so may also improve cognition, breathing and other end organ attributes.

In this chapter, we will see how the symptoms of chronic pain and fatigue tie into the cellular basis for inflammation caused by the loss of the capillary cell dance. Inflammatory influences that block this dance can be identified as those that affect the capillary cell from the inside out, from the outside in.

Outside- In Inflammation

Outside-in inflammation is caused by the macro environment we live in. These inflammatory mediators or free radicals come from the food or toxins we ingest, air we breathe, water we drink and the outside stressors that impact our emotional health and affect our sleep. Highly processed sugary-salty foods that are often packed with hidden transfats obliterate our intestinal microbiome, induce leaky gut, and form the foundation for serious chronic inflammation throughout our bodies. Being a couch potato, cigarette smoke, chronic alcoholism, and drug abuse all can increase risks for insomnia and stress and contribute to cascades of other chronic inflammatory conditions.

Outside-in inflammation can cluster attract and stack to accelerate inflammation when inflammatory mediator exposures link with each other. They are known as primary inflammatory mediator risks, first-line vascular inflammatory risk factors, or vascular inflammatory free radical seeds. They are notable in that they initiate or seed inflammation to endothelial or capillary-cell basement membranes and interstitial spaces. If not mitigated, they induce chronic inflammation within interstitial spaces and are linked to a persistent festering of free radical exposures. These exposures eventually induce arterial endothelial cell basement membrane thickening, increase shear (friction) within arterial lumens and separate the endothelial and capillary cell from its end organ partner.

Inside- Out Inflammation

The real damage these vascular inflammatory free radical seeds produce is from the inflammatory response they incite. That is, they plume or expand inflammation which is caused by the attraction of second-line inside-out inflammatory mediators (white blood cells, cytokines), also known as the immune arsenal towards the free radicals. These second-line inflammatory mediators intervene, upon request by capillary cells, to enter the interstitial space and expand inflammation for purposes of eliminating the offending inflammatory free radical(s). If not eliminated, interstitial space inflammation festers, which can then morph into a chronic inflammatory response. Over time, and with the right mix of inflammatory constituents within the interstitial space, this confluence can eventually organize and take on a life of its own. It eventually coalesces to become known an inflammatory matrix.

The Inflammatory Matrix

One the matrix is established, chronic inflammation begins to take on its own purpose and set an agenda. Central to its agenda is to convert the immune arsenal to its own doctrine. Doing so makes the immune arsenal increasingly hostile to capillary cell intent. The matrix begins a relentless assault on interstitial space mechanics to involve both the immune arsenal and mesenchymal cells. At a critical point, the inflammatory matrix creates enough inflammatory disruption within the interstitial space that the immune arsenal begins to work against the already compromised capillary cell. Shifting loyalty of immune arsenal is key to the inflammatory matrix being able to pirate permeability control away from capillary cell outer membranes. When this occurs, the interstitial space has been locked down in favor of proinflammatory influences. Capillary cells are now sufficiently zombied, immune arsenal and mesenchymal cells confused and end organs increasingly isolated from normal interstitial space homeostasis. When this occurs, the inflammatory matrix has completed its agendas and yields to the next phase of chronic inflammation, the emergence of the anti-organ.

The Anti-Organ

With the maturation of chronic interstitial space intent, the anti-organ can appear. The interstitial space is now firmly under its domain, and means that it can now implement venues within the interstitial space to perpetuate its power at the expense of the true end organ. This usually includes generous productions of scar tissue, attempts at thrombosis, and the introduction of different types of infectious agents, cancer cells and rogue autoimmune complexes. The coup d' etat is complete when some or all of these venues establish a foothold within the interstitial space.

Therein lies the deception that chronic inflammation creates. As immune arsenal is drawn into the interstitial space, with an intended purpose to eliminate vascular inflammatory free radicals, chronic inflammation smoke screens their intent and creates confusion about their purpose. The confusion causes immune mistakes which chronic inflammation uses to further disrupt immune arsenal intent. Eventually the mistakes create so much maladjustment within the interstitial space that the immune arsenal begins to work for proinflammatory influences. This is made easier by the fact that chronic inflammation has blocked the fluxing of capillary cell outer membrane permeability which has caused their mitochondria to seriously overheat from excessive energy combustion. The overheating cascades excessive production of superoxide free radicals, which then crosslinks to disable DNA to eventually cause enough DNA damage to reduce mitochondrial volumes. As energy support for outer membrane processes involving active transport evaporates, capillary cell outer membranes pseudocapillarize their receptors, voltage gradient and pore diversity. Game on for the inflammatory matrix to now use the confused immune arsenal to pirate capillary cell outer membranes.

The persistent demands for energy by capillary cell outer membranes, for the dispersal of immune arsenal into the interstitial space to mitigate chronic inflammation, block outer membrane fluxing of permeability, which then nullifies the capillary-cell mitochondrial pendulum swinging of combustion from energy to nitric oxide. With less nitric oxide production, capillary cell don't rejuvenate and end organ cells don't get the blood flow, vis-a-vis, oxygen and nutrient they want. The triple negative means, capillary cells don't rejuvenate, the interstitial space remains chronically inflamed and end organ function becomes increasingly impaired.

By the capillary cell fluxing permeability and acting as a stem cell and a pacemaker to its partners, the mesenchymal (helper cells) and end organ cells, the blocked dance also blocks important feedback loops that contribute to both the refurbishment and function of their interstitial space partners. It would also stand that as capillary cells fail to dance, so do their partners.

Once the anti-organ gains control, its venues work in the exact opposite direction and are diametrically opposed to those of the capillary and end organ cells. The production of amyloid and fibrous scar tissue from deluded mesenchymal cells makes it very difficult for the end organ to rally or find impetus to reverse course. Already void of feedback loop relationships with the zombied capillary cells, the laying down of fibrous scar tissue and amyloid creates yet another barrier between it and the capillary cell. As capillary cells pseudocapillarize and mesenchymal cells produce scar and amyloid, end organ cells have no choice but to atrophy (shrink) to conform to an increasingly hostile interstitial space. With the advent of other anti-organ venues, it only gets worse.

As the end organ declines there are increasing waves of fatigue and pain. The anti-organ, unleashes other venues that include hiding and breeding cancer cells, infectious agents and rogue autoimmune complexes. Thrombosis and hypoxic ischemic events involving the shriveled end organ increase and further torture its existence. The anti-organ's fuel are the numerous vascular inflammatory free radicals that continue to penetrate the interstitial space. Unlike the end organ, the anti-organ can thrive with or without oxygen. Therefore it is relentless in orchestrating the activation of clotting factors and platelets within the interstitial space to cause thrombosis. Thrombosis is like sticking a knife into the end organ as it asphyxiates relative to the amount of blood it does not receive as a result of the clot. Thrombosis can become a slow torture to an already reeling end organ. Sometimes the torture is slow. At other times, depending on the size of the occluded artery, it can be sudden and massive.

The collapse of the interstitial space and death of the end organ could come from anyone of a number of different events, that include thrombosis, explosive cancer growth or disseminated infections. The type(s) of venues the anti-organ employs is often predicated on what genetic dye is caste within a given end organ.

Anti-organ involvement from chronic inflammation in one interstitial space and end organ is likely also occurring with different twists elsewhere. Yes, chronic inflammation in one end organ may lead the inflammatory assault, but make no mistake, inflammatory cracks are occurring in all end organ interstitial spaces. This is because chronic inflammation, and how it fuels from vascular inflammatory free radicals, knows no vascular boundaries. Chronic Inflammation is occurring in all end organs from bone, liver, intestines, adrenals, kidneys, heart, brain, eyes, ears, sex organs and lungs to peripheral nerves, smooth muscle, tendons, ligaments, cartilage and skin. Even when one interstitial space of one end organ grabs the clinical headlines with an evolving cancer, autoimmune disease or infection, the truth is there are no interstitial space or end organ boundaries from chronic inflammatory influences.

In the cases of larger arteries, their end organ cells are the smooth muscle cells that contract or relax actin-myosin filaments to increase or decrease blood flow by increasing or decreasing lumen diameters. Large arterial vessel involvement in the chronic inflammatory processes compounds problems for upstream capillary cells as inflamed larger vessels downstream do not provide sufficient blood flows asked for by upstream capillaries. This further stonewalls end organ interests while perpetuating those of the anti-organ.

The Proposed Pathway of Chronic Inflammation leading to the Anti-organ

Let me summarize how chronic inflammation takes down the capillary cell dance:

• Outside-in inflammatory mediators, also known as first-line inflammatory mediators or vascular inflammatory-free radicals, increase, from a combination of lifestyle choices and genetic influences, populate within the bloodstream, migrate into the interstitial spaces of end organs, and seed to create an inflammatory response.

• As they accumulate and fester within the interstitial space, they attract inside-out inflammatory mediators, known as second-line inflammatory mediators or immune arsenal. These mediators are home grown which means they originate from endothelial cells, mesenchymal cells, bone marrow, lymph glands, spleen, or liver. When summoned from the blood plasma and sequenced to the interstitial space via the capillary cell they expand the inflammatory response to purpose elimination of the vascular inflammatory seed. The sequenced movement of immune arsenal (specific white blood cells, cytokines, immunoglobulins, complement and platelets), from blood plasma to the interstitial space, is accomplished by an elaborate display of exposed capillary-cell outer-membrane receptors and supported by energy and calcium ion release from mitochondrial combustion.

• With chronic inflammation, vascular inflammatory free radicals fester and cause a persistent expansion of immune arsenal into the interstitial space.

• The festering within the interstitial space from vascular free radical seeding, that produces the persistent expansion of immune arsenal, prevents the capillary cell from downshifting outer membrane permeability. Persistent permeability energy demands then blocks the pendulum swing of mitochondrial combustion. Chronic inflammation blocks the back-and-forth fluxing of capillary cell outer membrane permeability pivot which then prevents the mitochondrial combustion pendulum swing.