Chronic Fatigue and Long Covid key strategies

As we discovered in my last Newsletter, the Cell Danger Response (CDR) is initiated by the mitochondria, which, after sensing danger, divert the cell’s resources from promoting the normal function of the cell to creating a low-functioning cell that is more capable of neutralizing microbial threats (e.g., viruses) and surviving otherwise lethal stressors, by putting the cell into ‘hibernation’.

This is like putting the cell into hibernation mode, where around 95% less ATP (energy) is produced, leading to crushing fatigue. This is one of the reasons why many Chronic Fatigue sufferers use a high sugar diet, trying to increase the production of ATP by increasing the amount of glucose in the system. Unfortunately due to the mitochondrial dysfunction interfering with the pathway that produces ATP, this strategy does not work.

Once the CDR is triggered, cells warn the other surrounding cells to enter the CDR, but otherwise prioritize their individual survival and become disconnected from the tissue and organism they belong to. So, how can you get out of this chronic fatigue?

This cell disconnection causes cells to partially stop responding to a wide range of hormones like thyroid hormone or insulin, and also signals from nerves (which can be quantified through abnormal changes in things controlled by the nervous system, such as the heart rate and its variability).

Two ways emerge to look at the CDR. The first is that it is a remarkable adaptation that makes life possible by protecting and healing cells from each injury they encounter.

The other is that it is the disastrous root cause of chronic illness worldwide. The critical distinction between these two is that in health, the CDR cycle can complete itself and thereby exiting the CDR and leaving the body healthy again. While in chronic disease, however, something goes wrong and it can’t complete the healing cycle, trapping patients in an endless cycle of mitochondrial dysfunction and the resultant chronic fatigue.

Evidence is emerging that patients with long-COVID, also known as post-acute sequellae of SARS-CoV-2 infection (PASC), do not have a generalized defect in mitochondria. Instead of a generalized defect, long-COVID is associated with entry into a specifically altered state of hypometabolic (low metabolic) mitochondria function. The evidence for this comes from  measuring all of the metabolites that reflect the current metabolic function of the body.

In the case of hypometabolic disease survival states like chronic fatigue syndrome (ME/CFS), long-COVID, and related metabolic states, bouts of physical, mental and emotional stress can lead to setbacks called ‘crashes’ and post-exertional malaise. It is also worth noting that taking lots of supplements (that the body has to deal with) can also lead to setbacks; trying to rush the process can be counterproductive.

Cell Danger Response has three phases, and once something triggers the CDR, the following phases should occur:

•CDR Phase 1: An inflammatory phase where the cell seals itself off and eliminates microbial invaders. This should be short lived; a sustained CDR1 response creates chronic inflammatory disorders that are very injurious to the body.

•CDR Phase 2: A proliferative phase where missing cellular components and cells are replaced (e.g., via making new blood vessels, new cells, and recruiting stem cells). A long term sustained CDR2 can create chronic proliferative disorders like cancer.

•CDR Phase 3: An anti-inflammatory, reintegration and differentiation phase where the cell becomes able to resume its normal function and reconnect with the rest of the body. When CDR3 completes, the cells and tissues are frequently healthier than they were before initiating the CDR—a fundamental principle regenerative medicine utilizes to restore lost functionality.

This process is initially sustained by the cells signaling danger to each other (and later the body) with ATP, then is terminated by safety signals from the entire body via the vagus nerve. This termination requires phase CDR3 to re-establish the cell’s communication with the body and for the individual to exist in a “safe” environment that produces safety signals for the body.

Conversely, if the initial threat that triggered the CDR has not been eliminated, the body has evolved not to send signals to terminate the CDR. This is a key reason why the long-lasting synthetic mRNA (which continually produces the toxic spike protein) is so problematic.

Note: In addition to getting stuck along the progression of CDR1 → CDR2 → CDR3 → normal cell function, cells can also be shunted into the hypometabolic survival state mentioned above (e.g., this happens in chronic spike protein injuries, CFS, or chronic Lyme disease). Typically, for the first 3-6 months, the mitochondria that have switched to sustain the CDR can fairly easily switch back to their normal function. If the CDR persists past 3-6 months (which frequently happens in these illnesses), the mitochondria become much more challenging to switch back.

This model both explains why so many different things can trigger the “same” complex chronic illness and why so many different “healthy” practices (e.g., numerous supplements, stress reduction or good sleep) can partially improve but not resolve these illnesses.

Since this muli-factorial model is so outside our traditional one cause/one effect model of medicine, it is somewhat understandable many of these complex conditions are cruelly labeled as being “psychosomatic”, all in the patient’s head. This problem is further worsened both by the fact the CDR often creates depression or anxiety, while negative emotions cause the brain to signal danger, worsening the CDR, which in turn prevents the patient from embodying positive emotions that signal safety and resolve the CDR.

Rebooting The Healing Cycle

Treating the CDR is a relatively straightforward approach, by replacing things that signal danger with those that signal health (known as salugenesis – the origins of health) and directly blocking the signals for the CDR.
The six key elements of this health cycle are

1) Wakeful activity,

2) Nutrient intake,

3) Waste and toxin removal,

4) Social connection and positive social support,

5) Nature connection, and

6) Restorative sleep.

Absence of, or abnormalities in, any of these key elements of the health cycle can lead to disease, while their presence contributes to the building of a functional reserve capacity and resilient health over the weeks and months after injury or illness.
Some of the most important things for anyone seeking to facilitate the health cycle are as follows:

•Restore a healthy balance between the rest and relaxation (parasympathetic) and the fight or flight (sympathetic) branches of the nervous system—Excitatory (stress) circuits trigger the CDR and anxiety, while inhibitory circuits are used for calming and safety signaling. This is a crucial part of why stress reduction and positive emotions can be quite helpful for CDR illnesses. Unfortunately, CDR patients are frequently stuck in a state of chronic sympathetic over-activation and parasympathetic deficiency, a state of chronic stress.

•Restore normal sleep architecture (deep sleep), as this period is used by the nervous system to signal safety to the body (delta waves play a crucial role here). Unfortunately, an active CDR disrupts normal sleep patterns. Over the decades, countless integrative practitioners have consistently observed that restoring healthy sleep is vital for chronically ill patients but, unfortunately, often quite challenging to restore. See my article on restoring healing sleep here.

Additionally, one of the primary molecules that signals sleepiness to the body, adenosine, is a product of ATP being broken down by regular metabolic activity throughout the day. Caffeine, for example, keeps you awake by blocking the adenosine receptors in the brain. In many individuals, that effect can persist for hours after consuming it (which is one of the many things that may need to be addressed when treating insomnia).

•Restore the normal rhythms of the body (e.g., the circadian rhythm)—This concept is now relatively understood for the sleep cycle, and many leaders in the integrative medical field strongly advocate avoiding exposure to signals that disrupt the normal timing of the sleep cycle (such as blue light at night). However, sleep is not the only rhythm disrupted by modern technology.

This next point is absolutely vital for those with some form of chronic illness. The body requires pulsed rather than continuous signals to regulate itself. A frequent error practitioners in the integrative medicine field make is giving something they believe is “good” for you continuously rather than in a pulsed fashion; this can often actually reverse the benefit of an otherwise beneficial therapy. My colleague Dr. Mark Brudnak first looked at pulsing with probiotics and autistic children in the early 2000’s, finding that they responded better to pulsed treatments than continuous treatments.

This is also why recovering from a chronic illness typically requires “safe” periods free of external stressors and why it is so easy to reactivate a CDR pattern in the fragile period after the initial recovery from a chronic illness, which can be a really frustrating issue. It seems to take about three months, the length of a season, to solidify a new pattern within the body.

•The order of treating a CDR concomittant with an active danger (e.g., an infection) is complicated. Likewise, many things that seem restorative or cleansing to the body can often heavily backfire in CDR patients due to the additional signals each intervention creates in the body. Furthermore, CDRs often become more and more sensitive to additional triggers as the disease progresses. For these reasons, in patients with an active CDR, it is important to avoid anything that might create too fast a shift in their system.

To provide a simplified version of the process for these patients, typically, you have to either:
-Treat the CDR.
-Treat the active danger, then treat the CDR.
-Treat the CDR, the active danger, and then the CDR again.

Additionally, detoxification is often necessary to perform before any of these (and sometimes before that, a much lighter form termed a “pretox”), as are therapies that improve the existing fluid circulation (e.g., by improving the existing zeta potential of the cells). This is because poor circulation to cells can be a trigger for the CDR, and any toxin shift requires a working circulation to drain the fluids so they do not build up and concentrate in a specific area (this encapsulates why giving antibiotics to a patient with Lyme disease who has an impaired fluid circulation can be so problematic).

It is thus critical to recognize that while many therapeutic approaches can improve symptoms resulting from the CDR, it is critical to determine if the therapy you are currently undergoing moves you more into health, or makes you feel worse.

•The end organ signaling resistance to hormones and other growth factors created by the CDR is very important to be aware of. In addition to signaling therapies (e.g., thyroid supplementation) being ineffective, since there is a mix of responsive cells (those not in the CDR) and unresponsive cells in the CDR, those therapies can often create a dependence (e.g., insulin in diabetes).
Note: in these situations, using low doses of T3 in the range of 2.5 mg rather than regular doses of T4 (Synthroid) helpful. Also, in addition to normal thyroid lab tests, it is often necessary to test for reverse T3 to guide one’s treatment.
Furthermore, they will over-activate the body and create a variety of complications (e.g., iatrogenic side effects), many of which result from the still functional tissue being over-activated or the CDR’d tissue being activated when it was not ready to be activated. This is also what often happens if one attempts to increase poor mitochondrial function with supplementation rather than treating the CDR (which is reducing mitochondrial function as part of a normal adaptive response).

•Fasting (intermittent and long-term) somewhat helps turn down the CDR since a fasting metabolism reduces excessive immunological activity and inflammation. Fasting will trigger the body to eliminate sick cells (which are often trapped in the CDR and disrupting the rest of the tissue) through autophagy, but normally won’t eliminate all of them.

One of the great questions in this area is whether the ketogenic diet is or is not good for you (as there is evidence supporting both interpretations). A recent study showed patients respond well to ketogenic diets because the diet provides nourishment to cells trapped in the CDR. Conversely, it also suggests that the ketogenic diet is not what the body wants in normal health.

Once a danger (emotional, psychological, physical, bacterial or viral) activates a Cell Danger Response, the sensitivity of cells trapped in that state to additional dangers increases. Since the spike protein not only creates a significant danger but remains in place for a prolonged period, as repeated exposure to Covid infections, and as the vaccine mRNA was designed to resist degradation in the body, it causes existing CDRs to significantly worsen (best shown by the inflammatory flares frequently associated with Covid or the vaccine). This results in the reactivation of inflammatory health issues which were formerly in remission.

Systemic Regenerative Therapies

These are the readily available therapies that the regenerative medical field uses to systemically treat the CDR and are available without a doctor’s prescription.

1. Sunlight, Basic Foods, and Rest
These encapsulate typical things the body does while attempting to restore itself when you become sick (illness, to varying extents, triggers the CDR). It’s important to remember that potential triggers for the CDR include cellular starvation, a lack of blood flow to cells, and nutritional deficiencies.

2. Common over-the-counter supplements like Vitamins A, B, C, D, Zinc, Selenium, and Fish Oil
These do help, but be aware there are many quality control issues with supplements bought over the counter (e.g., most fish oil is rancid). It is important to get hold of high quality products from your practitioner in order to gain the most benefit for your health.

3. Targeted nutritional therapies (Practitioner level nutraceutical product lines, certain minerals or vitamins, amino acid complexes and specific peptides).
One of the challenges with supplements is that their quality greatly varies, and it is often challenging to find ones whose designers ensure both the quality of the supplement line and its ability to provide targeted energy to the body.

Certain trace minerals can be extremely important for restarting the system. Those are typically selenium (most common), molybdenum, and manganese; if a critical trace mineral is missing, cells can become unstable. Biotin (a vitamin) also fulfills this role for the hair. Additionally, amino acid deficiencies are a widespread cause of cells lacking the capacity to function correctly.

4. External light therapies, typical peptides (aluminum free).
Once we enter this category, the interventions have a high enough energy level to make dramatic improvements for patients. However, at the same time, they can also easily overwhelm a system that is not ready for them and need to be utilized judiciously.
Light—There are a lot of light therapies (typically red, blue, or infrared) out there. Many benefits have been observed with them, and red light therapy has been one of the treatments many have reported sometimes helps spike protein injuries. Generally speaking, blue light therapies tend to work to reduce inflammation and skin conditions. In contrast, visible and invisible red light (which can sometimes be inflammatory) tends to work in areas of depletion (e.g., a knee with osteoarthritis).

Peptide therapy—Since peptides provide signals for tissue production, it should not surprise you that they improve physiologic states where cells are being signaled to become dormant.
There are however two major issues with peptide therapy. First, they only signal production, so if other things are needed for that to happen, peptides are unlikely to work and may create harmful reactions instead by pushing the cells to grow when they aren’t ready to.
Secondly, there is immense variability in the quality of available peptide products, and as a result, there are highly inconsistent results in what each of them will accomplish.

When in doubt, liaise with your health care provider, or you can email Dr. Neil Wootten at [email protected]