Oxidative stress is emerging as the underlying mechanism of many chronic and acute illnesses. Oxidative stress is caused by an excessive build-up of reactive oxygen species in the cells. Reactive oxygen species can be released by cells during an immune response or they can build up within the cells by mitochondrial dysfunction. Extracellular release of reactive oxygen species creates a pro-inflammatory cascade that can be acute or chronic depending on the cause of build-up. Intracellular reactive oxygen species buildup can lead to intracellular protein, fat, and DNA destruction and eventually cell death. Cellular death leads to extracellular release and triggers inflammation. Research is now showing the initial step in the inflammatory response is triggered by excess ROS release in extracellular fluid. Normal levels of intracellular reactive oxygen species facilitate many normal functions within the cell. They act as a stimulator of the genetic expression of proteins and are conserved and used to break down cellular waste products. In the immune system, reactive oxygen species and certain enzymes are used to kill and break down foreign material.
ROS are produced in the mitochondria during ATP production as well as in cellular response to xenobiotics, and pathogenic organisms invasion (bacteria, molds, and parasites) of the body. Oxidative stress refers to the imbalance due to excess production over the capability of the cell to mount an effective antioxidant response.
Mitochondrial production of reactive oxygen species is due to inefficiency in the electron transport chain. As the body is metabolizing sugars, proteins, and fats for energy a byproduct is the creation of reactive oxygen species. It is normally controlled well by the antioxidant systems within the mitochondria but if complexes with the electron transport chain are compromised excessive build-up can occur within the mitochondria. Dysfunction of the mitochondria can be a threat to cellular health so many mechanisms will attempt to bring balance to the system but if the dysfunction is irreversible the mitochondria will release chemicals inducing cell death.
Xenobiotic production of reactive oxygen species occurs as the body attempts to detoxify these compounds. Xenobiotic chemical substances are foreign to animal life and
include plant constituents, drugs, pesticides, cosmetics, flavorings, fragrances, food additives, industrial chemicals, and environmental pollutants. It has been estimated that humans are exposed to 1-3 million xenobiotics in their lifetimes
Pathogenic organisms increase the production of reactive oxygen species as a result of cellular damage caused by a pathogen and as a result of the immune system releasing reactive oxygen species to kill invaders and clean up cellular debris. During this process, reactive oxygen species trigger an inflammatory response to activate the immune system to respond to the local threat.
Symptoms of Oxidative Stress
Oxidative stress can take on multiple forms as stated above. Symptoms can vary greatly in their acute and chronic presentation. Many of the symptoms are normal aspects of the healing response. Some of the symptoms develop into chronic degenerative conditions if prolonged. The causes of oxidative stress will also present differently as the mechanisms involved vary. The mitochondrial presentation will be different from the toxic effects of Xenobiotics and the immune-mediated response to pathogenic organisms will have its symptom presentation.
Mitochondrial oxidative stress will show symptoms of decreased cellular function, especially in higher energy cells such as the nervous, muscular, and cardiovascular systems initially. These cells will have decreased ability to produce energy and show symptoms of inflammation and decreased function. To fully understand the rest of this section it would be a good idea to read the Mitochondrial Function Blog.
The range of symptoms of mitochondrial oxidative stress depends on the cause. Oxidative stress occurs during vigorous exercise resulting in fatigue and muscle soreness, which self-corrects. The cause of oxidative stress during physical training is due to lack of oxygen delivery to keep pace with energy demand. As muscles are trained they will build the ability to deliver oxygen and simultaneously produce more mitochondria in the muscle.
Oxidative stress is a common issue we see in my clinic relating to the overuse of muscles due to sustained chronic postural stress. People who have desk jobs put excessive sustained demand on the neck and shoulder muscles. These muscles get overworked and do not get the rest needed to clear the oxidative stress-induced inflammation (trigger points).
Any condition which creates a high demand for energy production without sufficient oxygen delivery to the cells causes oxidative stress to some degree. COPD, Asthma, rapid elevation changes, lower respiratory illness, and any cardiac insufficiency illness will create increased oxidative stress from mitochondrial oxygen delivery insufficiency. The symptoms of these conditions are usually confined to the muscular system as soreness and fatigue with slight neurologic symptoms of confusion and mental fatigue. Extreme cases of oxygen depletion such as a stroke or heart attack will lead to oxidative stress-induced cell death.
Oxidative stress in the mitochondria can also be caused by the inefficiency of the Electron Transport Chain (detailed in the previous Blog mentioned). The 3 weak links of the electron transport chains are CoQ-10 Cytochrome C and cytochrome Oxidase Deficiencies of Coenzyme Q-10 which are commonly associated with statin medications or liver disease will result in oxidative stress within the mitochondria. CoQ-10 is produced in the liver and dietary intake is a minimal secondary contributor to necessary levels. In CoQ-10 deficiency conditions, the symptoms are slow in onset and more widespread. The mitochondria have amazing abilities at adapting to dysfunction in the short term, they will fuse (mitochondrial fusion) to help a distressed neighbor by pooling resources. Over the long term lack of Co Q-10 will become a systemic issue affecting the muscular and nervous systems as oxidative stress becomes an issue. The following is a list of CO Q-10 deficiency symptoms due to statin medications:
Common side effects
Side effects can vary between different statins, but common side effects include:
- feeling sick
- feeling unusually tired or physically weak
- digestive system problems, such as constipation, diarrhea, indigestion, or farting
- muscle pain
- sleep problems
- low blood platelet count
Uncommon side effects
Uncommon side effects of statins include:
- being sick
- memory problems
- hair loss
- pins and needles
- inflammation of the liver (hepatitis), which can cause flu-like symptoms
- inflammation of the pancreas (pancreatitis), which can cause stomach pain
- skin problems, such as acne or an itchy red rash
- sexual problems, such as loss of libido (reduced sex drive) or erectile dysfunction
Rare side effects
Rare side effects of statins include:
- muscle weakness (myopathy)
- loss of sensation or tingling in the nerve endings of the hands and feet (peripheral neuropathy)
- tendon problems (tendons are tough cords of tissue that connect muscles to bones)
Most of the above side effects are the result of decreased mitochondrial function in different systems and inflammation related to oxidative stress of the entire body. Also note some of the symptoms related to lack of function of the cells (due to lack of energy to function) such as hair loss, digestive issues, tendon issues, and neurologic issues. Treatment of these conditions is restoring the liver's ability to produce CoQ-10 and oral supplementation.
Cytochrome dysfunction results in a higher level of oxidative stress compared to that CoQ-10 deficiency. The job of Cytochromes within the electron transport chain is more elaborate than the rest of the structures involved. Cytochrome C is the rate-limiting step controlling the production of ATP and is the regulator of oxidative stress in the mitochondria. It also can initiate cell death if reactive oxygen species are getting generated at a dangerous rate. Cytochrome oxidase accepts the electrons from cytochrome c and terminates the process by adding them to oxygen and safely producing water.
The interesting part about Cytochromes is very little research is being performed directly concerning their dysfunction. Very rare genetic disorders occur at birth and are fatal early on in life. Theoretic research is showing that frequencies in the electromagnetic spectrum can enhance and inhibit mitochondrial function. It is believed to be occurring as a result of Cytochrome responses to varying frequencies of nonionizing energy. Cytochromes are chromophore molecules that share a structure called a Heme group similar to the hemoglobin molecule in the blood. Chromophores are commonly known in the body as pigments as they can reflect light but at the same time, they also absorb light frequencies. Research on red light therapy has shown it enhances mitochondrial ATP production and decreases reactive species production. The accepted mechanism is the vibrational frequency for the chromophores in the mitochondria are within the red light frequency of the electromagnetic spectrum. Red light activates the heme molecules within the cytochromes increasing their ability to transfer electrons efficiently. Studies of man-made frequencies such as from cell phones effect on mitochondrial function reveal decreased ATP production and large amounts of reactive oxygen species production. It is theorized these low frequencies alter the energetic vibration of the cytochrome molecules altering their function.
Symptoms of Cytochrome insufficiency leading to mitochondrial oxidative stress depend on multiple factors. Some people are more susceptible to non-ionizing energy resulting in radiofrequency illness. Some people can have exposures and not become symptomatic. Genetic factors have been ruled out because mitochondrial DNA is purely inherited by the mother. Research has not shown a susceptibility pattern associated with genetic transfer from the mother. The benefits some people have over others may lie in their ability to neutralize oxidative stress by intrinsic anti-oxidant production (cellular production). For example, 900 MHz exposure from a device may affect 2 people differently because one has a better ability to neutralize oxidative stress. For this reason, mechanisms of dealing with oxidative byproducts may probably be the factor that distinguishes one group from another. As we will discuss in the next sessions an added difference may be generalized oxidative stress in the body due to environmental toxic overload or immune activity relating to foreign invaders.
Environmental toxins can induce oxidative stress on cells through mechanisms that are direct, indirect, or involve the disruption of intracellular mitochondrial function. Toxins can induce a direct effect due to the nature of the compound being an oxidant. Exposure to oxidants can cause damage to the cells by the same mechanism as reactive oxygen species. An oxidant by definition is a compound that removes electrons from another substance. Our body tightly controls oxidative mechanisms in many reactions which are beneficial in many cases. Cells also employ reverse reactions in the same way called reduction which is the addition of an electron to a compound. The electron transport chain is a highly studied system of Redox reactions in which electrons are transferred during a physiologic process. Toxins can cause indirect oxidative stress by binding to other substances and changing that substances into an oxidant. The field of Xenobiotic toxicology is finding that one is hard-pressed to provide an example of a xenobiotic exposure that does not involve some level of oxidative stress. We are fortunate that our bodies are constantly battling to detoxify environmental exposures but if levels of exposure outpace our systems' abilities illness occurs.
Oxidative stress during infection is just recently been studied extensively. The depth of the topic will not be discussed in detail in this article. What does need to be understood from this article is that during acute and chronic infections the body is under sustained oxidative stress as a result of tissue damage release and the immune system release to destroy the foreign invader and clean up tissue damage. Research is even discovering that the mechanisms of antibiotic medications may lie in enhancing the production of immune-mediated reactive species production.
Combating Oxidative Stress
At the cellular level oxidative stress is controlled by many mechanisms to maintain a balance between oxidative and reductive compounds. To enhance this balance dietary intake of natural antioxidants is your best defense. Limiting your exposure to xenobiotic toxins would also obviously be just as if not more important. Eating a diet of non-processed foods. Wild-caught fish, grass-fed organic beef with high anti-oxidant organic produce. Limiting exposure to unnatural forms of electromagnetic energy such as WiFi, Blue Tooth, and cellular phones. Set Wifi router to turn off at night, keeping the phone away from your body, and place on airplane mode at night are good first steps. Spend time in sunlight especially in the morning and evening when the most beneficial electromagnetic energy is being emitted.