Present psychiatric and physical understandings
Covid-19 (by year onset), also called coronavirus because of its microscopic crown like appearance with spikes, has been formally named Severe Acute Respiratory Syndrome Coronavirus 2 or SARS COV2. It was first detected in China, possibly bat derived (animal to human transmission), but it has become a Pandemic, with human to human transmission, spreading around the world. Coronavirus can mutate and recombine (i.e. change) as was seen with SARS COV in 2002 and Middle East Respiratory Syndrome coronavirus (MERS-COV) in 2012 (1). However, SARS COV2 is more contagious (i.e. spreads rapidly or exponentially) between humans principally through respiratory droplets or contact, with even asymptomatic carriers. It is less lethal than SARS-COV with up to 10% or MERS-COV at up to 25% deaths, respectively. It enters humans thru a cell receptor called angiotensin converting enzyme – 2 (ACE2) which exists on the outer membranes of specific cells found in heart, testis, small intestine, lung, kidneys, nasal mucosa, nasopharynx, stomach, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, brain, etc. ACE 2 protein was found on lung alveolar epithelial cells (i.e. where air oxygen/blood vessels interface for absorption) and enterocytes of the intestine which are the absorptive cells lining the inner surface of the small and large intestine. Also, of concern is that ACE2 was found in the venous and arterial endothelial cells that line the blood vessels as well as arterial smooth muscle cells in all of the organs studied (1,2), whose inflammation could contribute to clots and strokes. This also suggests the possibility that the atrial blood supply of all these organs could be disrupted by inflammation and clotting.
Despite the presence of SARS-COV in blood, and ACE-2 on the endothelia of all organs studied, only a lesser number of organs become virus positive. Viral entry appears to require something more, such as a co-receptor (2) or perhaps related to density or level of the expression of SARS-COV-2 receptors? This observation may be crucial in understanding why the majority of exposed patients are asymptomatic carriers. They are spewing virus from their nasal cavities, but the viral entry into their bodies has been blocked to a lessor or greater degree by their immune system response, possibly beginning in their nose, or actually having a lower density of receptors (ACE-2). Though there is a spectrum of disease severity, milder symptomatic outpatients not only had varying degrees of cough, fever, and shortness of breath, but fatigue and myalgia (3). However, a loss of taste and smell appears to occur in 71% and 68%, respectively of patients who tested positive, before any other symptoms (4). Similar results, but with 6 patients reporting it as their only symptom (3), were obtained in a telephone survey of 202 outpatients positive for SARS-COV-2. Of these patients, 36.1% reported a blocked nose, 43.6% diarrhea, 44.6% muscle or joint pain and 68.3% feeling tired (3). In another study 50.5% of adults and 10% of children presented with digestive problems including lack of appetite, diarrhea, vomiting and abdominal pain (5).
The coronaviruses (including SARS-COV) depend on the binding of the viral spike to ACE2 cellular receptors. It has now been demonstrated that SARS-COV-2 uses the same ACE2 receptor, which is mainly involved in blood pressure regulation. This receptor can be blocked by a clinically approved inhibitor of TMPRSS2, but has never been directly tested for corona antiviral treatment (6). Moreover, the commonalities between SARS-COV and SARS-COV-2 infections are revealed by the use of convalescent SARS-COV patients serum antibodies moderately neutralizing SARS-COV-2 entry or infection (6).
A preliminary Chinese observational study of inpatients hospitalized for COVID-2 who were taking angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) prior to admission has been published. They suggest that the risk for all-cause mortality was significantly lower in the ACEI/ARB group versus controls. Moreover, the inpatients taking ACEI/ARB were more significantly associated to decreased mortality as compared to patients on other antihypertensive drugs (7).
The psychological and emotional issues, and associated factors have been reported from China among the general population and among health care workers (HCW) exposed to SARS-COV-2 (8,9). In the general population, female gender, student status, specific physical symptoms such as myalgia (muscle pain and achiness), dizziness, coryza (mucousy nasal discharge including white blood cells, which deters infection encouraging us to clear our nose by blowing it), and poor self-rated health status were significantly associated with a greater psychological impact of the outbreak and significantly higher levels of stress, anxiety, and depression (8). Another study of 1257 HCW treating patients exposed to COVID-19 reported symptoms of depression in 634 (50.4%), anxiety in 560 (44.6%, insomnia in 427 (34.0%) and distress in 899 (71.5%) (9).
Previous studies of SAR-COV infected survivors of the 2003 outbreak found persistent psychological symptoms (10-12). A Hong Kong study (13) of 90 SARS-COV infected survivors who were a well-educated, relatively young (mean age 41.1 years) group which included 27 (30%) healthcare workers (HCW) was completed 30 months after the initial episode. In the 90 patients, no permanent lung damage was observed, but 25% have varying degrees of death of bone tissue due to a lack of blood supply, which raises the question of vascular blockage clotting. Nine (10%) of these patients had one or more family members die of SAR-COV. The cumulative incidence of psychiatric disorders during the 30 month convalescent period was 58.4%, with 44.4% diagnosed with major depressive, 47.8% with PTSD, 13.3% with panic disorder, and 6.6% with agoraphobia or fear of places that causes panic, helplessness or embarrassment such as crowds, or leaving home alone. At the 30-month post recovery point Major depression was 13.3%, PTSD was 25.6%, panic disorder was at 7.8%, and agoraphobia at 3.3%. Thirty percent (n = 27) of the 90 patients studied were health care workers (HCW) of which 68.9% were married or cohabitating at the time of the SARS outbreak. One divorced and five patient’s spouses died of SARS, after the outbreak. During the 30-month convalescent period, the rate of unemployment increased from 3.3 to 14.4%, retirement from 0 to 4.4% and 22% were on some type of sick leave, with 7.4% applying for early retirement. It is understandable why the authors concluded that the initial and ongoing toll of this invisible illness was a “mental health catastrophe” (13). This increased risk for PTSD (another invisible illness) in SARS patients who were HCW was supported by another study (10). HCW who were not infected but cared for SARS patients also underwent severe psychological stress and even mental illness up to two years after the outbreak (14,15) as suggested previously in the China SARS-COV-2 studies (8,9).
As Mak and associates note, (13)
Understandably, SARS survivors, being the direct victims of this deadly infectious disease, were most affected. Confronted with this novel deadly infectious disease, the experience of witnessing adverse events during hospitalization, uncertainty regarding one’s prognosis and the need for ICU care all constituted a terrifying experience for SARS victims (16).
Thus, it is not surprising that none infected HCW (and possibly even some family members) who observed this disease treatment process feared that they would become SAR-COV victims, would also experience substantial psychological distress.
The early COVID-2 symptoms of loss of taste and smell reflects that we breath in the virus through our nose (and even our mouth). Thus, affecting our nasal cavity where the highest concentration of ACE-2 receptors exist in the adult body, as well as odor receptors which send messages via the olfactory bulb to the brain. Similarly, taste cells (taste buds) are located on the front and back of the tongue, soft palate, upper esophagus, etc.. would be exposed early by breathing, even while eating. Respiratory viruses, such as coronaviruses, can attack the nervous system, and they, as well as cellular and molecular mediators of inflammation, can bypass the blood brain barrier. For example, SARS-COV2 could enter the brain via the olfactory (smell) neural pathway originating in the nose (17,18). This could be associated with the nasal coryza reaction initially with nasal congestion and a runny nose, one of the body’s initial immune responses to allergies and infection.
An article in the Wall Street Journal by Daniel Hernandez reflects the public’s increasing concern about COV-2’s behavioral and neurological effects on the brain (19).
A patient in Japan had seizures. An airline worker ended up in a Detroit hospital, where doctors diagnosed her with a rare form of brain damage. Others reported auditory and visual hallucinations or losing their sense of smell and taste…
As the number of confirmed Covid-19 cases world-wide reaches two million, clinicians are realizing the disease doesn’t just ravage the lungs and hurt the heart. It also can, in a significant proportion of cases, affect the nervous system in little-understood ways.
Though a growing number of papers, doctors are chronicling brain inflammation, hallucinations, seizures, cognitive deficits and loss of smell and taste. It is unknown whether these are caused directly by the virus infiltrating the nervous system, or by the body’s immune response…. The range of effects could take decades to play out. Some epidemiological studies and lab experiments with other viruses suggest severe infections could set in motion molecular events that might increase the risk of developing neurodegenerative disorders like Alzheimer’s or Parkinson’s, many years later. The links are a matter of debate among neurologists and neuroscientists.
On Friday, Chinese doctors published a study of 214 hospitalized patients in Wuhan showing that more than a third had neurologic symptoms. The most common included dizziness, headaches, impaired consciousness, skeletal-muscle injury and loss of smell and taste. The paper-published in the Journal of the American Medical Association- also documented rare, but more serious effects including seizures and stroke…. The novel coronavirus called SARS-CoV-2 isn’t the only virus known to affect the nervous system. Research in humans and animals has shown that non-coronaviruses such as HIV, measles and certain influenza strains can infect the brain or affect its function through inflammatory responses elsewhere in the body. Laboratory studies have shown that other coronaviruses can infect nerve cells….
Past studies of SARS COV infections described visual and auditory hallucinations, depression, and manic disorders. Coronavirus RNA has been found in the autopsied brains of SARS patients and in those with multiple sclerosis. Serological immune assays specific for four different non-SARS human coronaviruses (229E, HKV1, NL63 and OC43) were antibody immunoglobulin (IgG) assessed in 106 voluntary patients with recent onset of psychotic symptoms including those with bipolar disorder and major depression, ages 18 to 45. Mean antibody levels were significantly greater for 3 of the 4 coronaviruses in the patient group of 106 as compared with controls, especially for HKV1. Coronavirus seropositivity and antibody levels were increased with both mood and schizophrenia-spectrum disorder diagnoses… but… were generally more consistently elevated with a schizophrenia-spectrum disorder diagnosis (e.g. schizophrenia, schizophreniform, schizoaffective, delusional disorder, psychotic disorder not otherwise specified, etc). There was no difference in antibodies between these patients and controls for influenza A and B viruses (17). In a study of non-recent onset (18) in 218 older patients (18 to 65 yrs.) with a history of mood disorder, past suicide attempts, depression and bipolar depression, seropositivity for influenza A, B, and coronavirus (NL63) were associated with a history of mood disorder but not specifically with depression, or with bipolar depression (18).
The Role Of Mitochondria in SARS-COV-2 and associated issues such as clotting
Symptoms such as sleep disturbance, fatigue, appetite disturbance, loss of interest in usual activities and decreased social interaction are observed in both sickness behavior and clinical depression related to viral infection (18).
Loss of energy, loss of motivation, chronic, unremitting fatigue, with or without muscle weakness and excessive sleeping or hypersomnia are cardinal symptoms of mitochondrial distress. Fatigue and related symptoms are often misdiagnosed as depression. Major depression may be the clinical expression for reduced mitochondrial respiration and impaired mitochondria-regulated immune response (20).
But what are our mitochondria?
Our mitochondria are the energy powerhouses of the cell. They could accurately be compared to armored nuclear power plants because they activate and safely contain (when healthy) the intense explosions required to cleave the high-energy bond between two oxygen atoms. These oxygen-cleaving explosions would cause devastating, widespread oxidative damage (akin to a nuclear meltdown) if they occurred anywhere else in the body. This catabolic oxygen combustion helps break down food (carbohydrates, proteins, and fats) and converts it into energy units called ATP (adenosine triphosphate), plus water, heat, and carbon dioxide…
The key point here is that mitochondria are exponentially better at producing ATP… and any physiological process that causes mitochondrial dysfunction can cause widespread cellular energy deficits and fatigue, adversely affecting virtually all organ systems including the brain (21).
Figure 1: Schematic of a mitochondria (22).
Figure 1: Schematic of a mitochondria (22).
Source: 22. Eirin, A., Lerman, A., Lerman, L. O.: Mitochondrial injury and dysfunction in hypertension- induced cardiac damage. Eur Heart J. 2014 Dec 7; 35(46): 3258–3266. doi: 10.1093/eurheartj/ehu436
The inner membrane is formed as Cristal or folds that increase its total surface area. Hypertension as an example, is one of the main risk factors for SARS-COV and SAR-COV-2, is “prominently associated with the loss of cardiolipin, a phospholipid uniquely found in the inner mitochondrial membrane and necessary for proper cristae formation… Furthermore, cardiolipin regulates mitochondrial dynamics and prevents the formation and opening of the mitochondrial permeability transition pore (mPTP), and release of cytochrome C from mitochondria to the cytosol (aqueous solution inside of the mitochondria) where it triggers apoptosis” (22). In other words, hypertension (high blood pressure) sets in motion or is part of a process whereby a hole is opened in the “armored nuclear power plant” of the mitochondria that can then be pierced and destroyed by a “bazooka” called SARS-COV-2.
Figure 2: (A) Schematic of proposed mitochondria-mediated mechanisms of disease progression. (B) Mitochondrial damage and dysfunction have been implicated in pathological conditions in many organs (22).
Figure 2: (A) Schematic of proposed mitochondria-mediated mechanisms of disease progression. (B) Mitochondrial damage and dysfun
Source: 22. Eirin, A., Lerman, A., Lerman, L. O.: Mitochondrial injury and dysfunction in hypertension- induced cardiac damage. Eur Heart J. 2014 Dec 7; 35(46): 3258–3266. doi: 10.1093/eurheartj/ehu436
Mitochondrial dysfunction can be caused by viral infection including SARS-COV and its individual viral protein 3a which results in mitochondrial death or apoptosis (23). In cellular homeostasis or health, there is a balance between the BCL-2 family protein, which are neuroprotective and Bax proteins which can be transformed to act like Darth Vader (death proteins) and can set off a cell-death cascade. This can occur in response to extracellular stimulation by stress, virus infection and by immune cytokines secretions which generally guide a healthy immune response. However, cytokines can cause inflammation, or an overreaction called cytokine storm. In healthy cells, Bax exist in one type of relatively stable molecular form in the cell’s cytoplasm, but with viral infection, for example threatening the cells health, it changes form along with increased levels of tumor suppressor protein P53. Studies reveal Bax moves to the outer membrane of the mitochondria where it inserts itself (i.e. one of the rockets released by the COV-2 bazooka). This causes the release of the cytochrome C, thus initiating apoptosis or cellular death (23). The reason the latter has been summarized is that long term valproate and lithium treatment often used for bipolar disorder at therapeutic levels, suppresses P53 and Bax expression but increases BCL-2 expression in rat brains cell cultures (24). Lithium and valproate also protected against methamphetamine induced reduction of mitochondrial cytochrome C.(23) There has been one report suggesting that lithium might be a potential treatment for SARS-COV-2, but none of the referenced in vitro studies involved clinically therapeutic levels of lithium concentrations (26).
Curcumin, the most important component of the spice Turmeric, has also been shown to have anti-viral effects. It reduces the release of cytochrome C and mitochondrial cell death. Its bioavailability can be increases by using it with black pepper, or cooking it in oil and pepper. (27,28) Curcumin can also decrease inflammation and mitochondrial dysfunction in obese mice with liver steatosis (i.e. excessive fat) (29). Non-alcoholic fatty liver disease (NAFLD) is obesity related and excessive liver fat accumulation damages mitochondria. Curcumin also decreases obesity toxicity induced mitochondrial dysfunction by protecting the liver (30). This allows healthier energy production which in turn affects obesity, one of the main risk factors for SARS-COV-2.
Another protein encoded by SARS-COV has been found (31) to adversely affect cellular mitochondria called open read frame – 9b (ORF-9b). It localizes to physically distort and manipulates cellular mitochondria and its function, thus enabling it to avoid/evade normal innate immunity defenses. Any virus is not Johnny one note, and has many modes of action which can change or mutate. What is being suggested here is that the life force and its immune defense depends on energy production and thus the importance of mitochondrial integrity cannot be overlooked.
Thiamine or vitamin B1 is one of the least recognized vitamins central to mitochondria and mental health. It was found deficient in 75 and 76% of type 1 and 2 diabetics, respectively and 29% of obese people. “Without thiamine, the whole mitochondrial engine slows to a halt.. can derail central and peripheral metabolism, induced tissue injury in regions with high metabolic demands, initiate build up of toxic intermediates like lactate, and impair myelination”… Other vitamins, minerals and nutrients that are supportive of mitochondrial function include niacin (B3), riboflavin, pantothenic (B5), folate (B9) where L-methyl folate maybe better for genetic variation with a family history of depression, methylcobalamin (B12), vitamins C,E, and D3, magnesium, L-carnitine, lipoic acid, Coq 10, zinc, iron, glutathione, essential fatty acid, and others can be used (20).
The following (figure 3) is from Science April 17, 2020 (32). With the exception of the lungs, eyes, and nose, all have very high cellular energy demands dependent upon intact mitochondrial formation: 1) the lungs act essentially as a very fragile air filter (e.g. black lungs with smoking). Here they are even more compromised since at the end of the respiratory tree are a single layer of cells, with a high concentration of ACE-2 receptors, in the shape of a tiny bubble called an air sac or alveolus. 6) The eyes and surrounding tissues are directly exposed to virus filled air droplets which is why health care workers wear clear plastic shields in front of their faces. Eye membranes including the inner eyelid most likely have ACE-2 receptors.
Figure 3: Schematic of some of the human body’s areas affected by SARS-COV-2. From Science (32)
Source: 32. Wadman, M., Couzin-Frankel, J., Kaiser, J., Matacic, C.: How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Science April 17, 2020.
7) Nose – the nose is the first air filter and first line of immune defense including coryza. If that fails to a lessor or greater extent, the virus can pass down the nasopharynx to the lungs where the interface of air, virus, and our blood supply in our alveoli can allow COV-2 along with any tiny clots from bleeding to spread throughout the body. Once it infects a cell in any area, the virus can take over the cells machinery (hijack) to multiply and infect new cells. New research (33) by Ziegler et al. reveals that “SAR-COV-2” spike protein binds ACE2, and in concert with host (our) proteases (an enzyme which breaks down protein) principally TMPRSS2, promotes cellular entry” or infection. Though interferones are produced by our body as antiviral substances, giving us protection while minimizing adverse effects or pathology, they can also be hijacked by COV-2 to increase the production of ACE-2 “in human nasal epithelia and lung tissues”… “to enhance infection” (33). This suggests that COV-2 not only self multiplies but increases the receptors it uses to enter us.
Various types of viruses have been found in blood clots during human infections (34,35). In the COV-2 pandemic “Many doctors now recognize clotting as a major feature of severe COVID-19.” Dr. E’na Marcia Negri, a Brazilian pulmonologist, “thinks that subtle clotting might begin early in the lung, perhaps thanks to an inflammatory reaction in their fine web of blood vessels, which could set off a cascade of proteins that prompt blood to clot and prevents it from getting properly oxygenated” (36).
Negri developed this idea after treating a woman whose breathing troubles coincided with circulatory problems in her toes. Negri’s team gave the woman heparin, a common blood thinner, and not only her toes but her breathing recovered. Negri wondered whether heparin could boost patients’ low oxygen levels regardless of whether they were struggling to breath. On 20 April, she posted a preprint detailing her hospital’s (successful) experience with COVID-19 patients. Patients with hypoxia received heparin, and the dose was increased if they had elevated levels of D-dimer, a blood marker of excess clotting (36).
Another critical marker is our microscopic blood platelets directly involved in clotting (stopping bleeding) and when low, we bruise easily or bleed. Italian researchers (37) found that low platelets, or thrombocytopenia, are associated with severe COVID-19 infection, and not milder cases. They concluded that low platelet count (i.e. more clots or clotting) is associated with increased risk of severe disease and mortality in patients with COVID-19, “and thus should serve as clinical indicator of worsening illness during hospitalization” (37). That suggests that the lower the platelet count, the more we are clotting.
Prothrombin is a protein in blood which when activated, become thrombin, a clotting promoter. It converts fibrinogen to fibrin which leads to the formation of a clot. Viral host cell proteases in mammals have been found responsible for activation and spread of various animal viruses (38). A protease was found in viral studies of chick embryo essentially identical to blood clotting factor x, a member of the prothrombin family, (38) also found in humans. This mechanism may play a role in COV-19 disease expression of increase clotting being observed presently.
From a practical point of view, physicians commonly prescribe aspirin 81 mg daily to prevent clotting and reduce the risk of heart attacks and stroke. However, it can increase the possibility of bleeding. Similarly, the Cleveland Clinic reports (39) that omega 3 fatty acids can reduce the risk of blood clotting because they help prevent blood platelets from clumping together. They are found naturally in higher concentration in fatty fish such as mackerel, salmon, cod, and herring. The Cleveland Clinic suggest eating a three ounce serving twice a week. High concentrations of course are available in omega 3 fatty acid supplements. Importantly, high levels of these essential fatty acids can cause bleeding (39).
The brain uses more energy per unit mass and has the highest concentration of mitochondria (20). However, the liver, intestines, heart, and blood vessels are heavy energy users which is even higher during an all-out viral assault involving their function. As Dr. Richard Boles reflects “mitochondrial dysfunction doesn’t really cause anything, what it does is predisposes toward seemingly everything” (20). A pertinent clinical example is the 53 years old Italian woman described in the Science article (32) with “classic symptoms of a heart attack”, but with no blocked coronary arteries. Nevertheless, her left ventricle (i.e. the strongest chamber in the heart) “was so weak that she could only pump her blood at one-third of its normal volume.” The latter could suggest impaired mitochondrial integrity with compromised energy production. The same article (32) also quotes a Dr. Mangelmurti saying “It’s very striking to us that risk factors seem to be vascular: diabetes, obesity, age, hypertension. It could be suggested that these risk factors are inter-related and may more likely occur as the result of relative degrees of impaired mitochondrial dysfunction (see figure 2, reference 22) which were briefly discussed previously except for age (43).
Mitochondria deteriorate with age, losing respiratory activity, accumulating damage to their DNA (mtDNA), and producing excessive amounts of reactive oxygen species (ROS). While for decades it was believed that ROS were exclusively toxic molecules causing damage, it is now accepted that low levels of some ROS species have signaling roles. Excessive and aberrant ROS generation, nonetheless, is one of the major consequences of mitochondrial dysfunction….
.…The mitochondrial free radical theory of aging postulates that the damage caused by accumulating ROS produced by mitochondria is the driving force behind aging. This theory is corroborated to some extent by the inverse correlation between mitochondrial ROS production and lifespan in mammals….
ROS are not the only aspect of flawed mitochondria that contributes to degenerating health though; ATP shortage, mutations in mtDNA, mitochondrial permeability transition pore (mPTP) opening, apoptosis, Ca2 + deregulation, inflammation, and altered fusion/fission dynamics are all mitochondrial factors that, while not necessarily acting independently, become disrupted in many diseases.… (43).
One of the concerns that arises with aging is the increased susceptibility to infections. In future research on treating immunological deficits, a mitochondria-centered approach may be in order. Beyond mediating apoptosis of infected cells, mitochondria are emerging as critical components of the innate immune response. It has been shown that the ATP needed for purinergic signaling (e.g. adenosine and ATP), T-cell regulation, and initial activation of neutrophils comes from mitochondria. ATP production and mitochondrial Ca2 + buffering are needed for antigen presentation and processing, and ROS are a part of the signaling pathway that activates inflammatory proteins. With the current rise of multidrug-resistant “superbugs”, other ways of combating infections grow increasingly crucial. Based on accumulating evidence, mitochondria may be viable therapeutic targets….
As mediators of immunity, mitochondria are consequently targeted by several viruses: Influenza A viral protein PB1-F2 induces mitochondrial dysfunction as a mechanism of crippling the innate immune response. The protein translocates across the outer membrane, accumulates in the inner membrane space, and causes a drop in mitochondrial membrane potential. This results in mitochondrial fragmentation, inhibits NLRP3 activation, and induces apoptosis. Accordingly, PB1-F2 translocation correlates with subdued innate immunity. The SARS virus also targets mitochondria. The virus-encoded protein ORF-9b localizes to mitochondria and triggers degradation of DRP1, MAVS, TRAF3, and TRAF6, thus evading the host immune responses.… (43).
Mitochondrial dysfunction with age makes the elderly more vulnerable to many illnesses including viral infections such as SARS-COV-2 (43). It appears that exercise, besides the vitamins and micronutrients discussed earlier, can be helpful in improving mitochondrial function and possibly viral resistance. Exercise improves mental status (attention/concentration, higher cognitive functioning, and short-term memory), sleep, and cardiovascular fitness indicators such as stress test heart rate and oxygen consumption in older adult (44). Similarly, rejection of the sick role, improved health outlook (44), and mood including decreased anxiety and an improved sense of well-being results (45). All of which can make people more resistant to infection.
How might we help ourselves? Importance of exercise, fiber, and meditation.
Recent research reveals mitochondrial dysfunction including mitochondrial uncoupling and reduced efficacy of adenosine triphosphate production (ATP), with ATP cell depletion, “are found in human muscle nearly a decade before accumulation of irreversible DNA damage that causes electron transport defects” (i.e. integral to ATP energy production). “New evidence points to reduction in activators of biogenesis” (i.e. tissue renewal and regeneration) and to degradation of mitochondria allowing accumulation of molecular and membrane damage in aged mitochondria. The early dysfunction appears to be reversable based on improved mitochondria in vivo and elevated gene expression after exercise training” (46).
Similar findings are found with neural stem/precursor cell (NSCs) proliferation or neurogenesis observed in the hippocampus (has a major role in learning and memory) of mice with treadmill exercise. Their decrease in neurogenesis begins in middle age, and exercise altered their brain chemistries in a manner favorable for NSCs “proliferation, survival, and maturation” (47). Yes, exercise is also brain food, but moderation is important in affecting the endogenous growth factor proteins that support brain plasticity optimally, called neurotrophins. Prolonged low intensity exercise, and moderate exercise, affects neurotrophins in a sustained positive manner, but higher intensity exercise “elevates the stress hormone, corticosterone (48). Moreover, there is a well-known higher incidence of upper respiratory tract infections (URTIs) among endurance athletes (49). Hardly helpful in the age of COV-2.
Exercise opportunities for the elderly are still quite limited in spite of internet classes for the rest of the population, including Zumba, Pilates, etc.. Asian countries including China, Japan, Singapore etc. encourage communal exercising, both in large inside and outside venues, such as Tai Chi (50). It is often called a “soft” martial art and is practiced for health and spiritual benefits. It is noncompetitive and slow paced, and it can be practiced for the entire lifespan. Yet, it burns as many calories as table tennis and more than surf boarding, while increasing strength, flexibility, body awareness and physical and mental health. For those not so inclined, taking a 30 minute daily walk ideally where there is nature (e.g. green and/or water) will be helpful. Nevertheless, everyone needs to exercise regularly, not only for aesthetics but for the prevention of illness such as obesity and diabetes. Exercise gurus need no guidance here except to mention that skeletal muscle produce myokines, small proteins which have immunoprotective and anti-inflammatory properties so that surprisingly muscle can act like an immune regulating organ.
The link between mitochondrial dysfunction, obesity and Type 2 Diabetes has been discussed (51). Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes mellitus (T2D) and obesity and both have been linked to decreased muscle mitochondria reproduction and their dysfunction. The uncoupled mitochondrial state is necessary for increased mitochondrial dependent ATP synthesis. Animal studies have established that excessive mitochondrial coupling is a central expression of mitochondrial “dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes” (52). What is impressive is the striking similarity of mitochondrial changes in obesity and diabetes to those found with age. Nevertheless, as with exercise, improved nutrition with dietary fiber may also be helpful.
Dietary fiber and its fermentation products, especially, the short chain fatty acids (SCFAs) acetate, butyrate, and propionate, have numerous beneficial effects. They can ameliorate chronic inflammatory diseases, improve immune responses beyond the gastrointestinal system, such as influencing the lung and brain, dampen immune responses, act on immune cells such as regulatory T cells, dendritic cells, neutrophils, macrophages, memory responses of CD8+ T cells, and T helper cell differentiation. SCFAs can influence metabolism in liver, muscle, immune cells, and adipose tissue (40). Moreover, Zhao and associates (41) in fermentable fiber studies with humans and mice found that the high fiber diet (HFD) specifically increased colon or gut bacteria with SCFAs that reduced type 2 diabetes symptoms as measured by glucose tolerance tests and hemoglobin AIC. When the stools from both patient groups was transplanted into germ-free mice, those receiving stool from the HFD patients had the best outcomes. These findings reinforce the importance of the gut microbiota, or all the organisms inhabiting the human digestive tract, as the mediator of health and change (41).
Figure 4: (40) Effects of a low fiber and high fiber rich diet.
Source: 40. Trompette, A., Gollwitzer, ES., Pattaroni, C., et al: Dietary Fiber Confers Protection against Flu by Shaping Ly6c- Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism. Immunity. 2018 May 15;48(5):992-1005.e8. doi: 10.1016/j.immuni.2018.04.022.
The enzymes in the mouth and upper small intestine such as amylase and ptyalin cannot break down (digest) prebiotic or fermentable fibers such as inulin. It passes relatively unchanged to the large intestine where it is fermented into SCFAs. Inulin is water soluble and found in many plants which use it to store energy in their roots instead of starch. Inulin has up to 10% the sweetness of sugar but only 25-35% of the food energy of sugar and starch with many added health benefits noted earlier. Not surprisingly, high performance inulin at 10 grams daily in type 2 diabetic women increased antioxidant capacity, while decreasing body weight and glycemic indices (62). A teaspoon is 4.2 grams and one teaspoon twice daily would be essentially 10 grams.
There are presently no studies available with a diet rich in fermentable fiber and any coronavirus. However, work has been previously published by Trompette and associates (40) which is clearly instructive in determining whether fermentable dietary fiber influences antiviral immunity. In mice born and raised on a low fiber diet, they compared a control group supplemented with cellulose (a poorly fermentable diet) to the test group on high fiber diet (HFD) supplemented with inulin. Both groups of now adult mice were exposed intranasally to influenza A virus (IAV) which uses the same ACE2 receptor as coronaviruses. HFD mice had prolonged survival and improved clinical scores. They also experienced reduced pulmonary resistance, related to milder airway constriction, increased elasticity and therefore better lung function. The control mice lungs’ had large accumulations of red blood cells in their lung tissue indicating destruction and vascular leakage. Other measures of immunopathology were decreased in HFD fed mice. Additional antiviral immunity effects of HFD or inulin (figure 4) included 1) alteration of the intestinal microbiota with increasing SCFAs especially butyrate. Moreover, “supplementing the drinking water with butyrate for 2 weeks prior to and throughout the infection resulted in protections similar to that elicited by a HFD”. 2) Prevention of excessive neutrophil (white blood cells) influx into the airways by decreasing CXCL1 (a potent neutrophil chemo attractant) produced by lung macrophages and monocytes. 3) Though there were more Ly6c- patrolling monocytes in the blood, bone marrow, and lungs, they were preferentially differentiated into alveolar and interstitial (between cells) macrophages with a less inflammatory “M2” phenotype also called “alternatively activated macrophages” (AAMs). This reduced airway neutrophils and damage. (4) CD8+ T lymph cell activation occurred with specific anti-influenza viral effect and a high cytotoxic cell killing capacity was found (40). There are two types of CD8+ T cells. Memory T cells that have been previously exposed to an infectious agent or a foreign body that they know how to fight and “naïve” T cells which have never fought anything. Because we have had no exposure to COV-2 before, the memory T cells are not able to mobilize. The battle is left to the new “naïve” T cell troops. Fortunately, inulin activates these T cells with specific antiviral and high cytotropic capacity making them potent viral killing T cells.
As Trompette and associates summarized (40):
… our data demonstrate that dietary fiber and SCFAs can protect against severe influenza infection by reducing tissue damage and by boosting adaptive anti-viral immunity. SCFAs have predominantly been associated with immunoregulation and the prevention of exaggerated inflammation; however, our work highlights a dual role of SCFAs. By tuning down excessive innate responses, promoting tissue-protective mechanisms, and stimulating specific adaptive immunity, dietary fiber and SCFAs can create an immune balance that ultimately protects against disease.
The importance of the microbiota in another study (42) is again revealed in their modulation and fine tuning of interferon which protects lung tissue in mice (all mammals) from viral infections. If the mice were given antibiotics which killed or disrupted the microbiota (dysbiosis), their lung tissue was more easily infected by influenza. If the antibiotic-exposed mice were given fecal material of control mice orally by a tube to their stomach (fecal transplant), they became more resistant. That is, it increased production of interferon proteins with various antiviral function and fine-tuned interferon viral resistance. (Figure 5). This reinforces the view that antibiotics are contraindicated in viral infections (e.g. COV-2) per se.
Figure 5: (42) The effects of antibiotics and fecal transplant in mice on influenza infection and interferon, and its receptors
Source: 42. Bradley, K. C., Finsterbusch, K., Schnepf, D., et al: Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection. Cell Reports. 2 July 2019, 28(1), 245-256.
Fear of and anxiety over the COV-2 invisible illness to which you may be unknowingly exposed or may be carried by you or someone close to you, has to some extent limited our other concerns. These included various forms of financial and job insecurity, hunger, housing, unemployment, etc. For the elderly, social distancing can become sensory deprivation called loneliness, disconnectiveness, and isolation. The latter apparently contributed to a surge in suicides among older adults in Hong Kong during the SARS-COV epidemic in 2003 (53). If history is useful, another surge of reported depression, anxiety and PTSD is forthcoming (10-16). This was observed previously in SARS-COV positive patients including HCW, as well as none positive HCW who treated COV positive patients. None infected family members may also be vulnerable. Calling older family members, friends and neighbors to say hello and inquire about their well-being is health care.
But, we also need to attend to our own emotions as they affect our physical health and our immune system. Mindfulness meditation (MM) may be used to help our mind not only deal with the stress of and anxiety over COV-2, but can help drive our immune system in a positive protective direction. MM is commonly defined as “the awareness that emerges through paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment” (55). MM is readily available on the internet, downloadable apps, blogs, or websites for use. It has also been defined as “a systematic attentional strategy to reduce cognitive vulnerability to reactive modes of the mind that might otherwise heighten stress and emotional distress”. Patients who have had COV-2, and their therapists relate that MM helped the patients be at one with their body so that they could meet their body where they were in their illness and its symptoms. This may seem counterintuitive, however, by nonjudgmentally reframing their anxiety, emotions, and thoughts, it seemed to keep them from making their symptoms worse. Moreover, a systematic review of randomized controlled trials of MM and the immune system revealed benefits (fig 6).
The levels of NF-KB which coordinates the inflammatory response and CRP or c-reactive protein, a commonly used measure of inflammation decreased. CD4+T lymphocytes (immune system white blood cells), protect the body against infection and promote tissue recovery. A decline in CD4+T lymphocytes is used as a “standard immune cell signal of disease progression in HIV patients.
Immune cell telomeres are protective DNA and protein complexes that function as caps to protect and stabilize the ends of eukaryotic chromosomes, which truncate during cell division. Shortened telomeres are a marker of immature cell aging and vulnerability to apoptosis, and are associated with poorer chemical outcomes and premature death in various age-related diseases. Telomere length is protected in part by the naturally occurring enzyme telomerase, which helps slow or reverse cell aging. Longer telomere and higher telomerase activity are thus considered to be salutogenic immune system profiles.
Figure 6: Mindfulness meditation and immune system biomarkers. This systematic review of 20 randomized controlled trials, comprising more that 1600 participants, revealed replicated, yet tentative, evidence that mindfulness meditation is associated with changes in select immune system processes involved in inflammation, immunity, and biological aging. Nuclear factor-kB, NF-xB; reactive protein. GRP.
Figure 6: Mindfulness meditation and immune system biomarkers.
Source: Ann. N.Y. Acad. Sci. ISSN 0077-8923
Social distancing is in direct conflict with human nature. We crave physical and emotional connection with friends and family who want to hug and touch each other. It is part of our DNA. Touch is essential for our emotional survival, especially for children (62). It is an expression of life, which is observed in the trauma of not being able to touch loved ones who are dying, our final loving contact. Or, watching children putting their hands in mirror fashion against the windows of their parents’, nursing or assisted living, rooms. We need to be touched and hugged as much as our pets since it fortifies us to live (62). It is the highlight of happy dinner parties. The internet reveals how people are trying to circumvent the virus to joyfully hug each other, referred to as “hugging machines”.
An attempt has been made here to provide some clarity in the everchanging chaos of SARS-COV, COV-2 information. Some possibly practical ways of responding to, or ameliorating Cov-2 as well as background information was presented. This included curcumin for its antiviral effects, low dose aspirin and omega 3 fatty acids as an aid to decrease clotting, inulin to drive a positive immune response, “a little fiber goes a long way” or possibly the SCFA butyrate taken directly has similar effects (54). Also, MM and exercise to reverse mitochondrial dysfunction which appears to be present in all of the risk factors for SARS-COV-2. Pertinently both influenza A (i.e. various types of the flu) and coronaviruses use the ACE-2 receptor to enter the body’s cells, and influenza produces lung damage similar to what is observed with SARS. The use of ACE inhibitors and ARBs (angiotensin receptor blockers), discussed earlier, were both found in hypertensive patients to lower the risk of influenza infections, if they had been taking these medications for more than 1.5 years (57). There was a continued increase in effectiveness each year of use for up to 10 or more years. Further research may reveal whether these findings (as well as similar findings earlier for SARS-COV-2 (7)), will provide insights into improved protection and prevention.
However, the big picture is that COV-2, and perhaps other new viral infections are probably here to stay, just like influenza which Hippocrates described almost 2500 years ago. We need to change our behavior and initiate research to find ways to strengthen and protect the body’s immune system, mitochondria and their organs so as to be more resistant and resilient to infections and their sequalae. For example, low dose aspirin alone did not prevent clotting (thrombosis) in one human study (58) and with one patient in a report of COV-2 cases (59). Yet, when combined with omega 3 fatty acids an additive beneficial (40% aspirin alone, to 62% with the combination) effect was demonstrated (58). The optimal protective combination, the dose, and type of omega 3s and aspirin for the general and specific populations are unknown. Moreover, it is necessary to know what is the best type and amount of exercise, MM, fiber, fiber based, or plant based diet, etc., to maximize our immune system’s and mitochondria’s preventative and protective functions. Remember, presently approximately 80% of infected individuals have no, mild, or moderate symptoms. Twenty percent become patients, of which around 5% are hospitalized. If we can move to enact public health, dietary, and other measures (e.g. online public dietary and exercise groups) to decrease hypertension, obesity, chronic lung disease, diabetes mellitus, and cardiovascular disease, we can not only increase the number of infected with no, mild, or moderate symptoms to possibly to 95%, but decrease the number that die. Our pollution and smoking have much to do with lung disease, (our lungs are not supposed to be a filter) and the rest are interrelated and mainly due to poor dietary habits and the lack of exercise.
Another vital issue is that people are putting off necessary elective surgeries, or delaying going to the hospital even with acute symptoms for fear of contracting COV-2. Hospitalists and surgical colleagues have shared that now patients more often arrive in a critical life threatening state, or paralyzed because of the progression of a stroke, than previously (59). This verges on insanity. Hospitals practice more precautions than the food markets people voluntarily go to daily.
Governments have mandated science based food additives, such as iodine to salt to prevent thyroid disease, to improve the public’s health. Dietary fiber has been shown to decrease type 2 diabetes mellitus (T2D), cardiovascular disease, and colon cancer and evidence is rapidly accumulating for infection prevention and improvement of mood (40, 41, 60, 61). More than 15 years ago the American Heart Association recommended that the ratio of carbohydrates to fiber should be no more than 10 to 1, respectively, and ideally less, because higher ratios were linked to T2D. Presently, many foods such as potato chips, crackers, white rice, many breads and breakfast cereals, pizza dough, pasta, etc., not made from whole grains would be excluded. However, this is easily remedied by adding fermentable fiber (not cellulose), and which has been found not to change palatability or taste (62). Fiber has been shown to increase our receptivity to vaccination, especially in the elderly, our most vulnerable group. Yet, vaccination is not the only answer as seen with the flu vaccines in that influenza can rapidly mutate and perhaps COV-2. A favorable possibility may lie in “tuning up” our bodies in ways similar to those suggested, and others, which reduces and prevents the risk factors to infections.
Little attention is being paid to the brewing “mental health catastrophe” seen in Hong Kong in 2003-2005, occurring here. There is so much insecurity with the disappearance of businesses including Hospitals, the middle class at food banks, the average worker including HCW being furloughed and fired, and the likelihood that their jobs will never exist again. This is the silent invisible suffering not seen since the Great Depression. There is a sea change with “tele-companies” thriving, forcing us to readjust and change. Nevertheless, COV-2 reminds us how really small planet Earth has become. Yes, “we are the people” and whether we like it or not, we are all in this together hopefully to initiate productive changes. The words of William James, the great American philosopher and America’s first psychologist, still ring true after 125 years (May 1895). “This life is worth living, we can say, since it is what we make it, from a moral point of view; and we are determined to make it from that point of view, so far as we have anything to do with it, a success”.
This article is not meant to be or interpreted as medical advice. All medical and health care decisions should be only be made between the reader and his or her health care provider. Comments and suggestions are welcome and will be printed and acknowledged in the next sequel which will be the result of all the information that I receive. After all, we are all in this together.