Bio Briefing—SARS-CoV-2, senescence and mitochondrial dysfunction

You should supplement magnesium...

Non-virus post coming later today or tomorrow. So many things going around, so many variables to take into account.

This entire post is more about long covid, or sequelae from Covid Infection.

SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response

Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production.

In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.

Whenever the authors refer to post-acute COVID-19 syndrome, they mean Long Covid. As I previously mentioned, there would be multiple ways for persistent, low-grade inflammation in Long Covid, and that the vaccines cause the same, just orders of magnitude faster.
On this paragraph, authors refer to one of the possible mechanism they uncovered, that SARS-CoV-2 infection triggers what you can basically call a loop of senescence via inflammatory signals between uninfected cells.

Cellular senescence is a state of irreversible cell-cycle arrest that can be induced by a variety of potentially oncogenic stimuli and thus is considered to serve as an important mechanism of tumor suppression3,12. However, unlike apoptotic cells, senescent cells do not die immediately and thereby accumulate throughout the body during the aging process2,12. Importantly, senescent cells are not merely nondividing, as they also develop a phenomenon called the SASP (ref.13) in which they secrete a variety of proinflammatory factors, such as inflammatory cytokines, chemokines, growth factors and extracellular matrix-degrading enzymes, into the extracellular fluid14,15,16.

Notably, this effect was greatly attenuated in the presence of the anti-tumor necrosis factor (anti-TNF) agent, but not the anti-type I interferon (IFN) agent or anti-IL-6 agent

Furthermore, similar results were obtained by depleting TNF-α in SARS-CoV-2-infected cells with short interfering RNA before collecting the culture supernatant

These results suggest that TNF-α plays an important role, at least partially, in the induction of the senescence-like phenotype of HDFs by SARS-CoV-2.

…p38 MAP kinase, a downstream signaling mediator of TNF-α 20, is highly phosphorylated in SARS-CoV-2-induced senescence-like…
Moreover, levels of p38 phosphorylation were reduced by treatment with the anti-TNF agent, but not anti-type I-IFN agent or anti-IL-6 agent.

These results, in conjunction with previous observations that TNF-α causes phosphorylation and activation of p38 and activated p38 induces p16INK4a expression and SASP in a DNA damage response-independent manner20,21,22,23,24, strongly suggest that SARS-CoV-2 provokes a senescence-like phenotype at least partly through TNF-α/p38 pathway activation.

Together, these results indicate that, at least in certain biological contexts, SARS-CoV-2 provokes paracrine senescence via cytokines secreted by infected cells. It should also be noted that the more virulent SARS-CoV-2 variant (B.1.1.7), first observed in the United Kingdom27, also induced a senescence-like phenotype in ACE2-HDFs with slightly faster kinetics than the original SARS-CoV-

This entire quote has a lot to unpack for the layperson, here they explain the pathways used on their model to test their hypothesis, which basically correlates with previous data and research.

Interestingly enough, this type of inflammatory response that leads to senescence, was not inhibited by either IL-6 (a major cytokine and inflammation driver), or via Type I Interferon (which is kinda like a broad spectrum, antibiotic), but achieved great inhibitory effect with TNF-α.
TNF-α is important to SARS-CoV-2 and lead to another extensive pathway, one that is more inflammatory long-term than short.

I would argue that parts of the Spike Protein itself, not only the infection, is driving this state in MANY Long Covid, either from infection, but mainly the vaccine (you can find many many of these on Twitter alone). Protein mimicry, persistence of pieces of the spike inside cells, presence of mRNA for weeks in lymph nodes, and germinal centers.

The real question is…which part.

Nevertheless, both our study and that of Lee et al. showed that the administration of senolytic drugs to SARS-CoV-2-infected rodents reduced the levels of inflammatory factors classified as SASP, implying that senolysis may be effective in alleviating post-acute COVID-19 syndrome. However, SASP has both harmful and beneficial effects3,12,13, and it has recently been reported that the removal of accumulated senescent cells in mice resulted in severe liver dysfunction

In this regard, it is interesting to note that hamsters infected with SARS-CoV-2 showed resistance to superinfection with influenza virus A H1N1 (Supplementary Fig. 3). Thus, it is also tempting to speculate that SARS-CoV-2-induced senescent cells may have some beneficial effects, depending on the biological context. Accordingly, a more rigorous analysis is needed to determine whether senolysis can serve as a preventive measure against post-acute COVID-19 syndrome.

And here we have the answer on how to deal with this specific aspect of the paper, using senolytic drugs or supplements. Fisetin is a powerful, and very strong one, and my favorite above all the others ( like Quercetin ). Another good one is… NAC…

But the best way to deal with this would be inhibiting or stopping the inflammatory signals using that p38/MAPK pathway early on, which leads us tooooooooooo.

Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel

Metformin Down-regulates TNF-α Secretion via Suppression of Scavenger Receptors in Macrophages

Berberine is an amazing analog to Metformin. Also, before the read asks, yes, this pathway, given specific cell signalling and responses can lead you to a Th17 state.

COVID-19 and Mitochondrial Non-Coding RNAs: New Insights From Published Data

No change in the expression of long non-coding RNAs was detected at any stage of the infection, but up to 43 small mitochondrial RNAs have their expression altered during the recovery from COVID-19. This result suggests that the SARS-CoV-2 infection somehow affected the metabolism of small mitochondrial RNAs specifically without altering the overall mitochondrial transcription. Despite these being only preliminary results on a small cohort, the analyses clearly showed that individuals infected by SARS-CoV-2 retain an altered expression of these small RNAs. This persistent alteration in the expression of small mitochondrial RNAs might be involved in the long COVID syndrome and further studies are needed to confirm the possibility.

These studies led researchers to hypothesize that the SARS-CoV-2 infection might lead to a redox imbalance, similar to what was observed in postviral fatigue syndrome, thus causing the symptoms observed in the “long COVID” syndrome

The hypothesis is that because of SARS-CoV-2 on mitochondrial metabolism (Miller et al., 2021), mitochondria non-canonical genes expression might be disrupted at some stage of the infection. To test this hypothesis, the following rationale will be used. Usually, changes in the expression of a gene of interest during a specific event, such as an infection, can be explained either by the gene being involved in that event, such as immune response, or that the gene expression is disrupted because of the event.

For example, to study long COVID syndrome, having data from muscle tissues would be ideal, and if they were available, they would have been included in this study. The fourth insight we can gather is that sex might be an important variant in the expression of mitochondrial non-canonical genes, as being male or female affects the expression of some small mitochondrial RNAs in the small cohort here analyzed. The last insight that we can gather is that populations effects might be particularly relevant when studying the disruption of mitochondrial genes expression, as different mitochondria haplotypes might have different expression (as seen in fruit flies before). In conclusion, despite having only preliminary results, and in need of further experiments, it can be concluded that the mt-sRNAs expression can change during the recovery from COVID-19, making these relatively unknown RNAs good candidates for further studies into their role in long COVID.

This paper is quite long, and very technical, if you are a clinician, specialist, or have a good understanding of this science, it can be an enlightening read. The entire paper focuses on genetic changes in Mitochondrial RNA and its biofunctions. By analyzing a data set that was proper to his hypothesis, the findings are pertinent to all stages of the disease, specially Omicron. Yes, Omicron isn’t driving cytokine storms, it ain’t destroying your lungs, but it is still SARS, even with that many changes on its Spike protein, it still holds bad sequences and mimicry.

By merely data mining social media, either by algo or by hand, you can find hundreds of people with some sort of dysfunction after Omicron. And if they are vaccinated, the sequelae can get even worse.

This isn’t a new perspective, as the author himself states, but it is an important step forward, especially in regard to Long Covid.

I myself held this angle for months.

John Paul @worldedge_group

@TheQuixoticEye @espressario @RWMaloneMD Hypothesis is, the spike use the same pathways as the virus, plus everything else we know about it It create different types of cell death, mess with mitochondrial function, ⬆️ ROS, in a bunch of people sudden or worsening diabetes Cascade into settings off any subclinical shit

In the end, as much as I wish I could find one, singular pathway to solve the entire etiology of this disease, I will never be able to, and nobody intellectually honest will say they will. The spike protein itself has so many things from different sources and so many protein (mimicry) like ours, it’s a Clausewitzian molecular war.

I still hold the opinion that this is one of the most significant aspects of this disease (and many others, in fact, mitochondrial dysfunction causes and worsens the progression of many many diseases). In my opinion, the massive replication of all current variants, the massive amount of ROS generated, persistent low-grade inflammation, and immune dysfunction contribute to this.

This dysfunction itself leads to senescence, one thing feeds the other. While not the end all, be all, for me, it’s one of the most important aspects, and why supplements that aid mitochondrial function brings relief to many people post-Covid (whatever degree of severity they find themselves in).

Know something that helps mitochondrial function and senescence. Magnesium (which most people in the entire planet is somewhat deficient on).

Populations in Low-Magnesium Areas Were Associated with Higher Risk of Infection in COVID-19’s Early Transmission: A Nationwide Retrospective Cohort Study in the United States

Many studies have confirmed the important roles of nutritional status and micronutrients in the COVID-19 pandemic. Magnesium is a vital essential trace element that is involved in oxidative stress, inflammation, and many other immunological functions and has been shown to be associated with the outcome of COVID-19 infection. Here, we conducted a nationwide retrospective cohort study in the United States involving 1150 counties, 287,326,503 individuals, and 5,401,483 COVID-19 confirmed cases as of 30 September 2020 to reveal the infection risk of the populations distributed in low-magnesium areas in the early transmission of COVID-19. Our results indicate that the average county-level COVID-19 cumulative incidence in low-magnesium areas was significantly higher than in the control areas. Additionally, a significant negative nonlinear association was found between environmental magnesium concentration and the county-level COVID-19 cumulative incidence. Furthermore, the populations distributed in low environmental magnesium areas faced a higher COVID-19 infection risk (RR: 1.066; CI: 1.063–1.068), among which females (RR: 1.07; CI: 1.067–1.073), the 0–17 years subgroup (RR: 1.125; CI: 1.117–1.134), the 65+ years subgroup (RR: 1.093; CI: 1.087–1.098), black people (RR: 1.975; CI: 1.963–1.986), populations outside metro areas, and counties with a smaller population experienced higher risk of infection by COVID-19 than other subgroups. Considering that the magnesium intake of about half the population of the United States is below the daily required dose, our study will contribute to the creation of long-term public health strategies to help protect against COVID-19

I have a few posts talking about the importance of magnesium, both for Covid Infection and general health.

Reduced brain function and immune disorder possible effects of long COVID-19

As a 33-year-old reporter for Kyodo News, my ailments related to COVID-19 continue to this day, more than a year after I recovered from the initial viral infection. Although I have seen slight improvements through treatment, I am still far from my former self.

In January, after an examination at the National Center of Neurology and Psychiatry in Tokyo, I was told I might be suffering from an immune disorder and reduced brain function due to the virus.

The examination I underwent included a brain perfusion scan, which is a test to determine blood flow in certain regions of the brain. It involves injecting radiotracers — radioactive substances that emit tiny particles — into a vein. A special camera is then used to track how the radioactive substance spreads throughout the brain to determine which areas are most active, which is believed to be indicated by blood supply.

The test can sometimes distinguish abnormalities in brain blood flow that a conventional MRI scan cannot detect, and is also used in examinations for dementia.

My test results showed lower blood flow in the frontal and temporal lobes, which govern language and memory, than people in my age range.

After infection with the virus, “autoantibodies” that attack the body may form if the immune response does not subside, a condition that has already been confirmed in COVID-19 patients with long-term aftereffects.

The center has long studied chronic fatigue syndrome (CFS), which causes various symptoms such as extreme fatigue and body aches. The presence of autoantibodies that disrupt the function of autonomic nerves is presumed to be one of the factors involved in chronic fatigue syndrome.

The entire article above is a good read, but it bears some hints to the causes of Long Covid.

I do expect in the coming months, if some nastier variants don’t pop up, people, especially among the vaccinated population, to develop different levels of chronic illness and decline in cognitive function.

You see, your body is full of redundancies, and it will metabolize its own tissues and even bones given the right circumstances. A few examples.

• If the patient doesn’t have enough ferritin stored inside his cells, no amount of SSRI will have any sort of effect, because the body won’t be able to metabolize and carry it.

• If the person lives under a state of hyponametria for too long, the body will demineralize its bones to produce the sodium it needs, leading to osteoporosis.

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