Long-haulers experience symptoms that limit normal function long after clearing the coronavirus. These symptoms include shortness of breath, fatigue, heart problems, dizziness, headaches, and impairments in mental health and cognition. An estimated 5% of people infected with COVID19 develop Long-Haulers Syndrome regardless of age and severity of symptoms during the initial infection phase. There are currently no effective treatments for long COVID, although research indicates that lingering inflammation is the main cause of most symptoms. New research indicates that coronavirus-infected cells transform into zombie cells and that this conversion is linked to long-term inflammation in long-haulers. Physicians have therefore begun to clinically test whether drugs that kill zombie cells are suitable for the treatment of Long-Haulers Syndrome. Below we will take a closer look at zombie cells and the freely available plant-based drugs used to kill these cells in Long-Haulers Syndrome patients.
Long COVID symptoms are linked to inflammation
The exact cause of Long-Haulers Syndrome has long been a mystery. But recent evidence indicates that many long COVID-19 symptoms stem from the persistence of inflammation after the SARS-CoV-2 virus has been cleared. While inflammation is part of the normal response to viral infections that helps the immune system clear the virus, there is no reason for inflammation to persist when the virus has been eliminated. So why do long-haulers maintain the inflammatory state? Some researchers speculated that this might have something to do with the zombie cells that the virus leaves behind as these cells have been shown to induce local or systemic (whole-body) inflammation.
Coronavirus-infected cells turn into pro-inflammatory zombie cells
The laboratory of Dr. Clemens Schmitt in Germany elegantly demonstrated that SARS-CoV-2 stresses the cells it infects to the extent that these cells convert into zombie cells. Shortly thereafter a Japanese study led by Dr. Eiji Hara confirmed these findings. Zombie cells are the nickname for senescent cells, which are known for their inability to proliferate and the production of a so-called senescence-associated secretory phenotype (SASP).
The SASP consists of hundreds of secreted factors, typically including not only cytokines, chemokines, proteases, growth factors, and lipids, but also noncoding nucleotides and exosomes. Studies over the past decade found that SASP factors can induce inflammation, fibrosis, coagulation, tissue damage, and stem cell dysfunction. What is remarkable with COVID-19 is that coronavirus-infected zombie cells somehow bring neighboring non-infected healthy cells into a zombie-like state, thereby further amplifying the SASP and the degree of local and systemic inflammation it causes.
Zombie cells negatively impact health and longevity
The existence of zombie cells was first noticed in the early 1960s by Leonard Hayflick. These intriguing cells were long speculated to be associated with aging and diseases that occur mostly at an advanced age. However, it took more than half a century for researchers to come up with evidence to support this theory.
The breakthrough came from 2011 and 2016 studies in mice published in the journal Nature, both from the laboratory of Dr. Jan van Deursen. These studies showed that zombie cells accumulate with aging throughout the body and that their elimination can slow aging, prevent age-related diseases, and promote longevity. The killing of zombie cells was referred to as “senolysis” and the drugs that do so were dubbed senolytics. Dr. Jan van Deursen’s work spurred the development of such drugs, which in preclinical studies (mostly studies in mice) have been shown to slow or prevent major diseases of aging, including atherosclerosis, dementia, osteoarthritis, and macular degeneration.
Two classes of zombie drugs for the treatment of COVID-19
Both the abovementioned COVID-19 studies used fisetin and quercetin to eliminate zombie cells. These natural compounds are flavonoids that are found in fruits and vegetables. They are freely available in stores as supplements. Both these zombie drugs were very effective in preventing death if they were administered within days after being infected with the coronavirus.
A zombie drug that falls within a different class is navitoclax. It is a small molecule that does not exist in nature and is produced by pharmaceutical companies. Navitoclax eliminates zombie cells by inhibiting proteins that belong to the BCL2 family. Zombie cells are so aberrant that they rely on this family of proteins to stay alive. In contrast to fisetin and quercetin, navitoclax had a limited impact on the survival of coronavirus-infected rodents.
Given the different outcomes of distinct classes of zombie drugs, it should be noted that both fisetin and quercetin have long been studied by researchers for a wide variety of health benefits. These earlier studies found both flavonoids to have powerful antioxidant, anti-inflammatory, and immunomodulatory properties. It is therefore conceivable that it is these properties that provide protection against coronavirus rather than their ability to kill zombie cells.
Fisetin clinical trials
Some have reasoned that the question as to how fisetin and quercetin provide protection against COVID-19 infection has become somewhat of a moot point with the availability of powerful vaccines and antivirals such as the Pfizer drug paxlovid. It is hard to argue against this, but the potential value of zombie drugs in the post-infectious phase of COVID-19 remains very high given the lack of successful treatments for Long-Haulers Syndrome.
There seems great promise for the use of zombie drugs for the treatment of long COVID-19 as highlighted by a recent new rodent study in which researchers specifically looked at inflammation that persists after coronavirus has been cleared, as is the case with Long-Haulers Syndrome. Using a zombie drug that inhibits BCL-family members on animals that had fully cleared the virus, the researchers markedly reduced the inflammation that persisted. The disadvantage of a zombie drug that inhibits BCL-family members is that it has serious potential side effects. Therefore, it is not freely available and only approved for the treatment of certain cancers.
This contrasts fisetin and quercetin, which both have an excellent safety profile and have been popularized to fight off aging and aging-related ailments through the work of Dr. James Kirkland. He is a physician and is currently involved in a dozen or so clinical trials testing the potential benefits of fisetin and quercetin, the latter of which is typically administered in combination with a low dose of the cancer drug dasatinib. Importantly, one of these trials is looking at the potential beneficial effects that the most unrestricted zombie drugs, fisetin, may have on long-term recovery of COVID-19 infected nursing home residents that had no, mild, or moderate symptoms. This trial should clarify the extent to which fisetin may be suitable for use by people that suffer from long COVID-19.
Fisetin as a natural substance and used as a drug
As mentioned, fisetin (also referred to as 3,3′,4′,7-tetrahydroxyflavone) is a bioactive flavonol molecule found in fruits and vegetables. The average daily intake of fisetin through food consumption is estimated to be 400 micrograms. The highest concentration of fisetin was found in strawberries (160 microgram per gram strawberries) followed by apple (26.9 microgram per gram apple), persimmon (10.5 microgram per gram persimmon), onion (10.5 microgram per gram onion ), grape (3.9 microgram per gram grape), kiwi (2.0 microgram per gram kiwi) and cucumber (0.1 microgram per gram cucumber).
The typical dose of fisetin that is used in ongoing clinical trials is 20,000 microgram per kg body weight, which amounts to nearly 1,500,000 micrograms or 1.5 grams of fisetin for a 165-pound person. This is about 3,750 times higher than the daily intake of fisetin through food. One may find the amount somewhat alarming. However, the over-the-counter (online) price of a 0.5 gram capsule of fisetin is as little as just over a dollar.
In the human COVID-19 trial, fisetin is only administered 4 times: first on two consecutive days and then the same one week later. The idea behind administering such few doses is the assumption that two short bursts of fisetin are sufficient to eliminate zombie cells and that, once they are gone, it takes a long time for them to come back to the extent that they can be of any negative impact on health again. The half-life of fisetin is in the order of 5-6 min which is considered very short for a drug. This means that zombie cells must promptly die after just a very brief encounter with the drug, and further adds to the mystery of how fisetin could possibly kill these cells.
It is important to keep in mind that fisetin has been reported to have a wide spectrum of molecular targets that belong to the most central cellular signaling pathways. For instance, it has been shown to inhibit mTOR, WNT, ERK, NFkappaB, and PI3K, while stimulating AMPK and TSC1/2. With its prominence as a zombie drug rising, it will be critical for researchers to decipher how it actually kills these cells. Of the 20 fisetin clinical trials that are listed on ClinicalTrials.gov, only a few are not directly linked to zombie cells. This is somewhat surprising given that for many years fisetin has been shown to be a chemotherapeutic agent in several types of cancers as well as a neuroprotective agent.
It will be interesting to see the outcomes of all the ongoing trials with fisetin. Although it will be difficult to interpret the mechanism of action if there is a positive outcome in any of these trials, the hope is that funds will be made available later to begin to decipher these mechanisms for each condition where fisetin is showing a therapeutic effect.