Antioxidant Archives - Page 3 of 3 - Dr. Nicholas L. DePace, M.D., F.A.C.C.

Mar 16 0

Biological Aging and Anti-Aging Mechanisms

Posted by joeobiso

The main risk factor for atherosclerosis or hardening of the arteries is usually aging. The older one gets the more likely they are to have atherosclerosis or hardening of the arteries and complications, such as stroke and heart attack. In addition, in regard to the nervous system, specifically the Autonomic Nervous System (ANS), there is also a significant risk factor for malfunction with degeneration of nerve fibers; including due to a lack of a proper blood supply to the very delicate fibers. This is a delicate interaction. The ANS, specifically the Sympathetic branch of the ANS, controls the vasculature and thereby proper blood profusion of the various tissues. It is the Parasympathetic branch of the ANS that senses tissue perfusion and drives the Sympathetics to that end. Normal, natural aging processes cause declines in the Parasympathetic and Sympathetic (P&S) Nervous Systems. Chronic disease and other chronic condition that cause oxidative stress, accelerate these declines. Reduced P&S activity to the vasculature reduces blood perfusion, which accelerates the aging of the nerves and tissues, which further reduces blood perfusion, and so goes the circle. Unfortunately, this is asymptomatic for up to two decades before patients feel it; at which time it is very late in the progression.

See the figure below comparing 300 healthy subjects over time and 500 chronic disease subjects over the same time. Notice that the upper curves show a gradual decline over time in the healthy subjects. The lower curves show a more rapid decline in the chronic subjects, then the decline virtually stops once the patients comply with therapy. Note, however, that the virtual stop occurs just above the horizontal broken line that indicates Cardiovascular Autonomic Neuropathy (CAN) which is end stage autonomic dysfunction and increased mortality risk (a 50% greater chance of heart attack or stroke in the next two years as compared with age-matched patients not demonstrating CAN). Note, DAN is the abbreviation for Diabetic Autonomic Neuropathy (also known as Advanced Autonomic Dysfunction in non-Diabetics). DAN is the precursor to CAN.

Eventually, age catches up with the chronic subjects and their decline parallels the healthy subjects with one important difference. For the healthy subjects the Parasympathetics are a little higher than the Sympathetics. This is reversed in the chronic subjects. A little more Parasympathetic activity in the geriatric population is known to be cardio-protective and is associated with lower morbidity and mortality risks. The more Sympathetic activity in the older chronic patients is associated with greater numbers of co-morbidities (25% more), prescribed pharmaceuticals (37% more), and life-threatening risks (e.g., Major Cardiovascular Adverse Events, or MACE, 18% more). In addition, with aging we see more small fiber inflammation and subsequent decrease in density of small fibers, which carry sensory pain and autonomic impulses. For both P&S decline and small fiber decline, early intervention often slows, significantly, the decline of nerve function (see figure below). In the case of the P&S Nervous Systems, early interventions may return a patient to the normal path and perhaps buy back up to 20 years.

Vascular aging causes degeneration and hardening of the arteries and degeneration of the nerve fibers which ultimately affect every organ creating end-organ changes; particularly, the heart, brain and kidneys are very susceptible. In general, age dependent injury to the vasculature and the nerve fibers becomes more manifested in the fifth or sixth decade of life. However, some people develop this more prematurely, such as diabetics or individuals with high genetic lipid disorders, or other genetic disorders. Some individuals have aging of their fibers and blood vessels more rapidly than other and, therefore, their biological age progresses faster than their chronological age.

There are certain noninvasive tests and blood test and biomarkers that can assess how the aging process is progressing. Perhaps, the most well known is the length of the telomeres. Telomeres are repetitions of DNA sequences that protect the end of chromosomes. With each cell division, the telomere is shortened and at such a point when they get below a critical length cells will be susceptible to death. As a telomere is shortened, one can get a higher incidence of heart disease, coronary artery disease, and cerebral vascular disease.

Other mechanisms, such as DNA methylation and low-grade inflammation may accelerate the aging process. The most common inflammation marker that we measure is C-reactive protein. Interleukin-6 is also another factor, which can be measure and be reflective of increased biological aging. However, there is no one blood test that can indicate whether an individual’s nervous system or vascular system is aging prematurely or more rapidly.

Recently, the leaky gut disorder has become a very popular topic and has been associated with many changes in the ANS and malfunction and degeneration of the ANS. Gut or gastrointestinal dysbiosis (microbial imbalance) has been linked to increase mortality risk and to disease. Increased gut permeability alters the microbiotic composition; that is the composition of one’s intrinsic bacteria in their GI tract. Toxic metabolites, if they leak through the cell junctions, can enter the blood stream and cause significant damage to blood vessels and nerves in the long term. Breath tests and various urine tests after ingesting specific compounds can detect Chronic Intestinal Bacterial Overgrowth (CIBO) syndromes which if not corrected can be detrimental to vascular and neural structures.

Many noninvasive tests can assess whether one’s vascular system or neural system is prematurely aging. We particularly like to assess HRV testing modalities especially coupled with respiration to assess Parasympathetic and Sympathetic power. Sudomotor testing can assess small fiber integrity, inflammation and deficiency. Carotid intimal thickness measures the thickness inside the carotid arteries and can also assess plaque burden, volume and density, which can be a surrogate for atherosclerosis and vascular aging. Endothelial dysfunction, which can be derived from measures of ultrasound flow-mediated dilatation, or other similarly noninvasive techniques, which are easily available to clinicians in a laboratory and can demonstrate a malfunction of the small cells lining the arteries as one ages. Calcium phosphate crystals deposited in the inner layer of the artery or the arterial intima, which is related to atherosclerosis, can be assessed with various tests. Commonly used is a CT scan of the heart in which one calculates your Coronary Artery Calcium Score (CACS). These are tests that can be obtained quite inexpensively and give a scoring system and assess the risk of future cardiac events and your degrees of potential atherosclerotic burden. This test correlates well with coronary artery plaque burden.

Tests that measure arterial stiffness and velocity in the arteries, such as carotid-to-femoral pulse wave velocity or brachial-to-ankle pulse wave velocity can give an indication of how stiff the arteries are and how they are aging. A high pulse wave velocity increases risk of cardiovascular disease and mortality from other causes. Hypertension can promote arterial aging and rigidity as can high cholesterol, sedentary lifestyle and poor diet, such as high meats and saturated fats, high salt intake and high refined sugars. Cigarette smoking is also a major culprit. While alcohol in low quantities may be protective for vascular endothelium, high quantities can be deleterious and can accelerate vascular aging. Sleep habits are also important in regard to aging of the blood vessels and nerves in the body.

We strongly promote a Mediterranean diet with high fruits and vegetables, nuts, seeds and legumes, and moderate alcohol consumption with flavonoids and antioxidants, such as with wine products, omega-3 intake with fish. In fact, omega-3 and fish oils have been shown to potentially decrease telomere length shortening and may have significant anti-aging properties.

There are many natural behavioral and pharmacological strategies which have anti-aging potential on the nerve fibers and blood vessels. Behavioral strategies include moderate alcohol consumption, exercise 150-200 minutes a week, weight reduction, diet high in antioxidant contents such as the Mediterranean diet and even supplements with antioxidant properties such as Alpha Lipoic Acid, which is extremely beneficial to nerve fibers, specifically autonomic nervous system fibers, or small C fibers. Cofactors with methylfolate and B vitamins are extremely beneficial also in preserving small fibers and even regenerating growth of them when they are deficient.

We have used Beetroot, L-arginine and L-citrulline as nitric oxide-producing compounds to better enhance endothelial function and preserve endothelial integrity and keep the blood vessels healthy. These produce nitric oxide by various mechanisms. As one ages, nitric oxide declines in a linear fashion, which is detrimental to the blood vessels. High vegetable and fruit intake is also associated with improving endothelial function and decreased arterial stiffness and decreased blood pressure.

Other studies have shown arterial function is less stiff and improves with flavonoids and cocoa, tea, coffee and wine, also in fermented dairy products, nut, seeds and vegetables. Olive oil and monosaturated fat has been shown to be extremely beneficial as an anti-inflammatory agent and endothelial-improving agent.

Key pathways to be regulated in the aging process that should be targeted are the mechanistic target of Rapamycin (mTOR) and Adenosine Monophosphate Activated Protein Kinase (AMPK). By inhibiting the mTOR and activating the AMPK, arterial stiffness can improve and blood pressure control can become better.

Regular moderate exercise to strengthen bone helps to keep calcium in the bone and reduce the calcium in arteries which reduces atherosclerosis, thereby reducing arterial stiffness. Vitamin K₂ (not ‘K’ but ‘K₂’) is a new consideration in the anti-aging process. Vitamin K₂ works to redirect calcium from the soft tissue (e.g., arteries) to hard tissue (e.g., bones). However, you must check with your physician to ensure that you are not at risk for blood clots. Vitamin K₂ may increase the risk of blood clots.

Metformin is one of the most prescribed medicines for diabetes. It has antioxidant effects in addition. Besides increasing insulin sensitivity, Metformin beneficially activates AMPK and beneficially inhibits mTOR. Endothelial function, vascular stiffness and carotid artery calcium have been improved with Metformin. Metformin has cardiovascular mortality benefits independent of its blood sugar lowering results. In addition, there has been data to suggest it can prevent certain types of cancer such as colon cancer. Perhaps the best agent to prevent cancers is the Mediterranean diet which has been purported to reduce at least 16 types of cancer. Resveratrol is a polyphenol naturally present in grapes and berries and especially red wines. It also activates AMPK and inhibits the mTOR pathways and has been very beneficial in protecting blood vessels and with antioxidant effects protecting nerve fibers. In animal substances, Nicotinamide Adenine Dinucleotide has been shown to have anti-aging effects on the blood vessels.

Anti-inflammatory agents are being developed to beneficially affect nerve fibers and blood vessels. More research is needed in that area. One of the most unappreciated anti-inflammatory agents are Omega-3 fatty acids, such as from or fish or krill oils; especially the compound Eicosapentaenoic Acid (EPA) in fish oils can reduce heart attacks and strokes, up to 25% as found in one study; even on top of statin therapy.

Gut dysbiosis contributes to inflammation and abnormalities of the ANS and the vascular system. Probiotics have been suggested as being useful in regulating gut dysbiosis as has certain antibiotics.

Risk reduction medicines used in heart disease, such as Aspirin, Statins, and Renin Angiotensin System blockers may have additional anti-aging potential.

Stress reduction and good sleep habits have significant effects on reducing oxidative stress and improving nerve fiber function and reducing degeneration of nerve fibers and improving blood pressure, endothelial function and arterial stiffness. Relaxation techniques, such as meditation and yoga have been found to be extremely important in this regard.

We specifically use what we consider therapeutic quantities of Alpha Lipoic Acid, L-carnitine, and Co-enzyme Q10 in treating many of our patients with autonomic dysfunction and have found improvement in autonomic neuropathy testing parameters over a period of six months in these patients in our laboratory. By combining these antioxidants, which we consider a Mitochondrial cocktail, as they produce more ATP energy molecules in addition to being good antioxidants, with Nitric Oxide producing compounds in appropriate concentrations (L-arginine, L-citrulline and Beetroot Extract), we believe we keep both the nerve fibers and arterial/vascular vessels from degenerating and aging. By lowering LDL cholesterol below 70 and by keeping LDL molecules from being oxidized with the use of antioxidants, by exercising and weight reduction to raise beneficial HDL levels, the vacuum cleaner of the blood vessels, we believe that we can affect reversal of Atherosclerosis in many patient’s especially when anti-inflammatory agents, such as statins (Rosuvastatin) is added in selected instances.

One needs to discuss all of these ideas and concepts with their personal physician who knows their case in detail to recommend what lifestyle, dietary, and pharmacological supplement and other additions or alterations in their regimen need to be done.

Feb 06 1

Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Posted by joeobiso

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ME/CFS is a common and very debilitating disease for which the origin, or etiology, is unknown. While there is some controversy about the exact cause or causes, much has been learned in the last 20 years. One widely held theory is that patients with a genetic predisposition and abnormal bacteria colonization, or dysbiosis, experience a gradual development of lymphocytes which are known as B cell clones which are susceptible to autoreactivity. Normally these B cells produce normal antibodies in the body. However, during unusual circumstances a triggering event such as a viral or a bacterial infection can cause these B cells to become autoreactive and produce autoantibodies. Therefore, there was some belief there may be an autoimmune mechanism which begins evolving and causes this disease process.

ME/CFS is a chronic disease that usually has lasted for more than six months. The result is post-exertional fatigue, unrefreshing sleep, memory and cognitive disturbances (“Brain Fog”), and oftentimes Autonomic Nervous System dysfunction (typically involving Parasympathetic Excess, an abnormal increase in Parasympathetic activity in response to a Sympathetic challenge or stress). Usually the stricken individual was very active prior to the onset of the disease. The disease usually persists as a chronic condition. Females are affected more than males. As many as 8 million Americans may be affected. While the cause of ME/CFS is unknown, many factors are through to contribute to the development of the illness, such as: (1) bacterial or viral infections, or (2) physical or emotional trauma, including from an accident, concussion, immobilization, surgery, trauma, or even a significant emotional stress such as loss of a loved one. Genetics may also contribute, and a genetic link with common environmental exposures, such as infectious or toxic has been postulated. Identical twins have a higher incidence then fraternal twins. Environmental factors, such as molds or toxins may also be a trigger to ME/CFS. However, no one common cause has been identified. This is because the population is heterogenous. Patients are affected at different ages and have different presentations.

Dysfunctional energetics at the cellular level is believed to be a common mechanism. Disturbed muscle function, metabolism, mitochondrial function, immunity, signaling, neurological, and adrenal and gut health are involved. Specifically, abnormal metabolism regarding the mitochondria has been demonstrated. Urea Cycle dysregulation, Tricyclic Carboxylic Acid (TCA) Cycle disturbances, and dysregulation of Amino Acid metabolism are also involved. Also, gut microbiota disturbances have been identified. In regard to Mitochondrial dysfunction, studies state that ATP8 levels have been both noted to be reduced and elevated, and resting ATP8 synthesis rates have been variable. However, studies on isolated Peripheral Blood Mononuclear Cells have shown that under stress such as Hypoglycemia there is inefficient ATP8 production in Chronic Fatigue patients but not in normal controls. This was demonstrated by Tomas and coworkers in 2017. Therefore, while resting ATP studies show that production may not be significantly abnormal in ME/CFS patients as compared with controls, it appears that under stressful situations, such as Hypoglycemia, the situation is different when one analyzes peripheral blood mononuclear cell ATP production. ATP is the energy molecule of the cell and of the body and is produced in the Mitochondria, which are the energy factories of the body.

Mitochondria are organelles, or components of cells, which are very active and contain their own DNA contents separate from the nucleus of the cell. Elevated oxidative stress has also been demonstrated in many subpopulations of patients with ME/CFS. Increasing oxidative stress has been demonstrated with testing products which are the result of oxidative stress, which include increased isoprostane, increased oxidized LDL levels, and increased iso-prostaglandin F2 levels. Also, reduced protective antioxidants, such as glutathione levels have been reduced in populations of patients with ME/CFS. Oxidative stress is produced when free radicals are produced in the mitochondria of cells in abundance during stressful situation and in essence cause a chemical burning reaction in damaged tissues.

Figure Legend: Schematic diagram showing various viral pathogens potentially associated with ME/CFS and possible molecular mechanisms altered by these pathogens that can contribute to ME/CFS development [[i]].

Plioplys and coworkers demonstrated lower levels of serum total Carnitine, free Carnitine, and Acetylcarnitine compared to healthy controls, and the lower level correlated with the more severe disease and ME/CFS patients. Carnitine is an important natural component in transporting Fatty Acids across the Mitochondria cell membrane to continue the process of fatty acid oxidation, which also produces ATP molecules.

In regard to ATP molecules, Mayhill and coworkers measured Mitochondria function and ATP production in Neutrophils and developed an ATP profile test. More elements of the ATP profile are abnormal in patients with ME/CFS. Again, this reinforces the fact that there are abnormal energetics occurring within the Mitochondria of cells. They state “our observations strongly implicate Mitochondrial dysfunction as the immediate cause of chronic fatigue symptoms. However, we cannot tell whether the damage to Mitochondria function is a primary effect or a secondary effect to one or more of a number of comorbidities, for example, cellular hypoxia or oxidative stress, including excessive peroxynitrates.”

[i] Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Translational Med. 2018; 16: 268, doi:10.1186/s12967-018-1644-y.

Figure Legend: Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and P_i are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidized form NAD⁺ and its reduced form NADH + H⁺ in carrying and transferring protons (H⁺) and electrons (e⁻) [[i]].

Key reports on ME/CFS have shown abnormal metabolites produced which demonstrate disturbed Amino Acid metabolism, dysregulated lipid metabolism with possible glycolysis impairment, possible Pyruvate Dehydrogenase (PDH) impairment, Urea Cycle dysregulation and overall TCA cycle substrates provision deficiency and reliance these cells for alternate fuel sources. As noted, Mitochondria function has been shown to be abnormal and the Electron Transport Chain, specifically if Complex IV is inefficiently compensated for the up-regulation of supporting pathways.

[i] Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009; 2(1): 1–16.

Abnormalities in B cells have been linked to mitochondrial disturbances and as gut microbiota and physiology. Autoimmunity has been little researched but has been performed on a subtype that is especially comorbid with Irritable Bowel Syndrome, which is seen in many Chronic Fatigue patients. Autoimmune evidence has been strengthened by the fact that there is a decrease in the natural killer cell cytotoxicity in patients with ME/CFS. Natural killer cells are Granular Lymphocytes which attack viruses and bacteria foreign to the body. In addition, the autoimmune evidence is supported by autoantibodies which have been noted against various transmitter receptors, both Muscarinic receptors and Beta receptors. A high incidence of these receptors has also been found in patients with Postural Orthostatic Tachycardia. Specifically, autoantibodies against the Muscarinic and Cholinergic receptors #3 (M3) and autoantibodies against the Muscarinic and Cholinergic receptor #4 M4) are elevated in 20-30% of all patients suffering from ME/CFS. Other studies have shown Beta-1 Adrenergic Receptor Autoantibodies and Beta-2 Adrenergic Receptor Autoantibodies along with Alpha-1 Adrenergic Receptor Autoantibodies, the same autoantibodies which we find in a significant number of patients with Postural Orthostatic Tachycardia Syndrome.

Testing for these autoantibodies is expensive, and it is not proven that immunomodulating therapy or steroids may be effective in these patients although there is some data that low-dose Hydrocortisone does improve patients with ME/CFS. There is also data that B lymphocyte cell depletion with a drug known as Rituximab can result in clinical benefit also. Also, an immunoabsorption technique which removes Beta 2 receptors and depletes them has been shown to be effective. This supports a cause and effect relationship with autoantibodies against receptors and removing them as a clinical response. This improvement in patients has been seen with Chronic Fatigue. In one study, immunoabsorption removed Beta 2 Adrenergic Receptor Antibodies in patients with ME/CFS and showed clinical improvement in memory in symptoms. Some of these patients had long-lasting improvements, while others had short lasting improvements. These are only pilot studies and more research is needed. Other studies have also shown higher autoantibody levels against M1, M3 and M4 Acetylcholine receptors and Beta 2 Adrenergic receptors compared to controls.

Impairments of the Hypothalamic-Pituitary-Adrenal system (considered a portion of the Autonomic Nervous System) have also been reported. There has been noted decrease in Adrenocorticotropic Hormone sensitivity of Adrenal cells expression of negative feedback mechanisms. Some patients with ME/CFS have low Cortisol levels and improvement with low-dose Hydrocortisone has been shown in these patients. In and to hormonal dysregulation, Autonomic dysregulation shows a strong association with ME/CFS. Some studies have shown that more than 90% of patients with ME/CFS have Orthostatic Intolerance. This is strengthened by the fact that many patients with Postural Orthostatic Tachycardia Syndrome (POTS) have similar autoantibodies to patients with ME/CFS. Blood pressure or heart rate regulation abnormalities are seen particularly in adolescents with ME/CFS and many experience symptoms of Orthostatic Intolerance as noted. These patients have worsening symptoms when they get upright posture and improvement when they lie down.

The association of Ehlers-Danlos Syndrome and Autonomic Dysfunction with high frequency of ME/CFS has been intriguing. We believe that there is a genetic predisposition to patients with Ehlers-Danlos Syndrome and Hypermobility spectrum disorders, and they are susceptible to develop Autonomic Dysfunction and Chronic Fatigue after exposure to certain triggers, such as viruses, bacterial infections, emotional stress, trauma, and concussions. Indices of inflammation are also noted to be increased in the populations of patients with ME/CFS. Increased production of various proinflammatory cytokines produce symptoms of fatigue, fevers, adenopathy, myalgias, and arthralgias, sleep disturbances, cognitive impairment and mood disturbances. Infections can trigger or initiate an autoreactive process affecting brain and energy metabolism in people genetically predisposed and patients with abnormal dysbiosis. Patients experience a gradual development of a B cell clone prone to autoregulation, and this may lead to autoimmunity.

Some patients have abnormalities of levels of immunoglobulins. Increased levels of IgA and in some cases, IgM have been noted, and these have been directed against endotoxin components of gram negative bacteria and may be the cause of increased gut permeability noted in many people with ME/CFS.

Exercise is the hallmark treatment for improving patients with ME/CFS. Given that Parasympathetic Excess is a typical Autonomic Dysfunction, usually “low-and-slow” exercise is recommended. Some experts in the field feel patients should exercise no more than two to five minutes at a time followed by five minutes of rest so not to damage skeletal muscle. However, “low-and-slow” exercise, such as walking slowly at no more than 2 mph for 40 minutes, every day for 6 months. No running or jogging or weight lifting or anything else that would raise heart rate too fast. Even if biking or rowing, the motion is still as if walking at no more than 2 mph. This is to re-train the Parasympathetic nervous system to accept small stresses, then larger stresses may be (re-)introduced. For some patients, this is still too stressful. For those days in which a patient simply cannot lift their head off the pillow, supine exercises are recommended, see figure below.

Antimitochondrial cocktails with antioxidants, such as Alpha Lipoic Acid, Coenzyme Q10 and L-carnitine have also been proposed by many experts and some patients are significantly benefited by these cocktails.

In regard to inflammation within the Central Nervous System, there is a glial activation or microglia activation which induces Nitric Oxide and superoxide production of free radicals. These cause neural excitation and neurodegeneration of tissue. Glial activation causes the chronic pain and allodynia in hyperalgesia via the impact a bidirectional signaling mechanism.

In regard to the unrefreshing sleep, we have already discussed the Hypothalamic-Pituitary-Adrenal Axis and the Hypocortisolism. Two meta-analyses have shown an attenuated Cortisol awakening response which may contribute to this morning feeling of non-refreshing sleep.

In addition to exercise and antioxidants, a ketogenic diet, which is high fat and low carbohydrate and limits calorie restriction, or a fasting diet has been recommended. This form of diet has variable results.

Recently from Stanford, a new blood test which produces a stressful environment to white blood cells, in this case mononuclear cells, was developed by Dr. Davis. It appears that patients with ME/CFS have a very high abnormal gradient or electrical charge when exposed to a salt stress environment then cells from normal individuals. Researchers are working arduously to develop these types of test, so we have more objective and easy ways to diagnose ME/CFS. ME/CFS must be differentiated from other entities that have other symptoms which are active participants in causing a malaise, such as collagen vascular disease, cancer, anemia, depression, thyroid disease, drug or pharmacological effects, and other metabolic and infectious diseases.

We believe that mitochondrial mutations or chromosomal mutations in susceptible people may cause ME/CFS. We believe that an autoimmune mechanism may be operative, where in some cases infections induce a normal immune response, but the pathogens may be close enough to our own receptors to cause them to be similarly attacked. After this, additional infections or physical or psychological stress can intensify both the mitochondrial energy deficits and the autoimmunity, and this can create a vicious cycle of fatigue. Patients can present with pain, brain fog, disability and poor exercise tolerance. These are direct or indirect symptoms of Parasympathetic Excess. The association of autoantibodies with similar autoantibodies with POTS and autonomic dysfunction syndrome in ME/CFS patients is not simply coincidence. Note, the Parasympathetic nervous system controls and coordinates the immune system. It may be possible that Parasympathetic Excess causes overactive and persistent immune responses that may lead to autoimmunity. Studies have shown that positive autoimmune tests also show mutations in Mitochondria genes that play an important role in the five mitochondrial respiratory complexes (I, II, III, C & IV; see figure above) in the Electron Transport Chain that produces 90% of the body’s energy with ATP.

The overlap with Hypermobility syndrome, Chronic Fatigue and Autonomic Dysfunction with Orthostatic Intolerance or Parasympathetic Excess states leads us to believe that there is mechanism at the cellular level, which causes an acquired Mitochondria Dysfunction with abnormal energetics producing energy from the body, and that the insulting agents that trigger this are in may cases infectious or inflammatory and can be worsened by emotional stress or trauma stress. They produce a state of inflammation known as oxidative stress which produces energy depleting agents (including oxidants) similar to autoimmunity. Authors have shown that oxidation of critical parts, for example, the Pyruvate Kinase Enzyme System can affectively block the transition of Glycolysis to Aerobic Metabolism, and this demonstrates a biochemical feasibility mechanism. Therefore, the autoimmune model involving the oxidative stress and acquired Mitochondria Dysfunction appear to have significant overlapping features when one looks at all of the studies that have been done on these populations of patients with ME/CFS.

What does this mean in terms of helping the patient? More studies need to be done in terms of using immunomodulating agents in trials, such as IVIG, Corticosteroids and B cell depleting therapies. More work is required assessing the types of exercise programs that are most effective, along with the types of diets that are more effective. The typical American Diet, highly processed foods, full of chemicals, together with the high levels of Psychosocial stress in the American lifestyle may be more of a cause of Chronic Fatigue, than anything else. More is required to study the components and dosages of Mitochondria cocktails that utilize antioxidant agents to see which are most valuable. More work needs to be done to stratify the ME/CFS patients into different phenotypes or categories, as this is a heterogenous group of patients. These patients have different presenting symptoms with different organ systems being more dysfunctional than others.

REFERENCES

1 Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Translational Med. 2018; 16: 268, doi:10.1186/s12967-018-1644-y.

2 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009; 2(1): 1–16.

Jan 29 1

Maintaining Antioxidant Balance

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Oxidative stress is a process whereby, Free Radicals that are produced by the body, cause injury to the tissues themselves; especially one of the most important organelles in the cell. The organelle that produces energy: the Mitochondria. Oxidation is the process of burning, think of fire, or rusting, think of iron. While oxygen is very important to the body, just like anything else in life, too much is not healthy: too little fire does not heat or cook, too much fire destroys, just enough fire sustains life. Oxidative stress is the process of burning healthy cells or cell structures, like Mitochondria. A common example of a Free Radical is a loose Oxygen ion. These loose Oxygen ions look to attached themselves (thereby neutralizing themselves) to other loose Oxygen ions or other molecules that are chemically or electrically suited to bind with them. Most of the time Free Radicals are not healthy; however, under the correct circumstances and at the correct time, Free Radicals are very useful. An example of ow they are used is by the immune system as a first defense to “burn-out” any new infections. Another common example is in programmed cell death to “burn” away damaged or useless cells.

It seems ironic, however, the largest producers of Free Radicals, in healthy cells, is the Mitochondria themselves. Just like any power plant, there is waste (pollution) generated in the process of producing power. Mitochondria are the power plants of the cells and the body. It produces Adenosine Triphosphate (ATP) as the energy molecule, and some of the waste products (pollutants) are Free Radicals. Under healthy conditions, the body uses these Free Radicals to advantage, as mentioned above. Under unhealthy conditions, the body requires Antioxidants to neutralize the Free Radicals that are not used. Under chronic conditions, the body tends to need more than it is able to produce. In all of these conditions, there is an appropriate Antioxidant-Oxidant Balance that sustains health. While the exact amounts are unknown, fortunately there is no such things as too many Antioxidants. It is like having “too many” fire extinguishers. The less used the better and if they are never used, they are not wasted. To that end, a well-established and maintained pool of Antioxidants is always healthful.

The body has natural Antioxidants to sequester, or neutralize, Free Radicals to prevent oxidative stress from injuring tissues and destroying cells. Natural Antioxidants include Vitamins A, C, & E, Glutathione, Selenium, Alpha Lipoic Acid (ALA) and Coenzyme Q-10 (CoQ10). Many scientists feel that ALA is the ideal antioxidant because it is both a lipid and water soluble (it can dissolve in both lipid and water environments) and can cross the Blood-Brain Barrier. It is absorbed rapidly through the Gastrointestinal (GI) tract high up in the digestive system and it is immediately available to neutralize free radicals quickly. It has also been shown to recycle Vitamin C and Vitamin E in the body. Vitamin C is only water soluble and Vitamin E is only lipid soluble. Because ALA is both liquid and lipid soluble, it can pass the Blood-Brain Barrier and increase available brain energy. Not only can ALA recycle Vitamin C & E but also Glutathione. Glutathione is probably the most important intracellular Antioxidant.

The mechanism on how Glutathione is recycled is very complicated. Glutathione is an indispensable Antioxidant and is synthesized within the Mitochondria and consists of three Amino Acids, Cysteine, Glutamic Acid, and Glycine. Glutathione is not easily absorbed orally and cannot pass through the Mitochondrial membrane so easily. Therefore, anything that preserves the body’s natural production of Glutathione and keeps the concentration up is valuable. This is where ALA comes in as a very important Antioxidant. It recycles Glutathione and replenishes the body’s stores. Glutathione is a very important component of several enzyme systems in the body that are organ-protective from disease. There is some data to suggest that ALA is also an excellent chelating agent and protects us from heavy metals, although this is beyond the scope of this discussion.

In regard to the nervous system, ALA is probably the most important Antioxidant protecting neural tissue. There is an abnormal protein known as Alpha-Synuclein which is highly expressed in neuronal Mitochondria. It causes neurological damage in diseases such as Lewy Body Dementia, Parkinson’s and in a condition known as Neurogenic Orthostatic Hypotension. It may also be operative in diseases, such as Diabetes, Hypertension and Dementia. ALA suppresses neurological intracellular accumulation of Alpha-Synuclein proteins. Therefore, it is extremely important. It is believed that Orthostatic Dysfunction disorders, which can cause autonomic disability, ALA may also be important by preventing the accumulation of Alpha-Synuclein proteins.

CoQ10 is also an extremely important Antioxidant in the human body. Whereas ALA is extremely important in protecting neural tissue, CoQ10 is extremely important in protecting cardiac and vascular tissue. There are many studies which have shown its importance in Congestive Heart Failure states. CoQ10 is an essential lipid soluble Antioxidant which protects cellular membranes and also circulates lipoproteins against Free Radical-induced Oxidative Stress. When cholesterol molecules become oxidized, they are more readily taken into the artery walls to cause atherosclerotic plaques and CoQ10 is one of the Antioxidants which protect against the oxidation of lipid molecules.

CoQ10 is an essential component of the electron transport chain which functions as an electron carrier and produces ATP, the energy molecule of the body. Therefore, CoQ10 is important for preserving the body’s energy. There are many different randomized trials of CoQ10 supplementation, including chronic stable Heart Failure. Many different methodologies have been used. However, CoQ10 is a biologically feasible protective mechanism to preserve the heart function. We have seen this to be the case, empirically, especially for patients who have had surgery. Literature has shown there is increasing interest in using CoQ10 for the treatment of Mitochondrial disorders because it improves ATP regeneration. We have found the combination of CoQ10 and ALA to be especially helpful in improving objective measures of autonomic dysfunction in patients who have dysautonomia and have been tested in our autonomic lab and served as their own controls.

Oxidative stress and inflammation contribute to most human diseases. Mitochondrial damage can also give rise to abnormalities in the immune system. There is a complex interaction between oxidative stress and cell division and aging. More research is needed in this area. However, the abundance of data suggests that Antioxidants are beneficial in maintain good health. That is not to say that a diet that is rich and high in Antioxidants such as the Mediterranean diet may not be the first preferred mechanism of these protective compounds. However, we believe that appropriate concentrations and supplements of Antioxidants, specifically CoQ10 and ALA, are important for maintaining proper balance of oxidants and antioxidants and in preventing nerve and cardiovascular tissue damage.

We believe that antioxidants are important in preserving ATP production by Mitochondria and maintaining energy in the nervous system, the brain, the heart, and the vascular system. By reducing or improving Orthostatic Intolerance syndromes, Antioxidants are part of a complex program which involves exercise, diet, stress reduction, proper sleep and hydration. All together this program is very beneficial in improving Chronic Fatigue symptoms.

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