Could SARS-COV2 accelerate biological age ?

Original article published on august 30th 2021 in french. 

Do you know the word "senescence"? In biology, senescence is the physiological process that leads to the degradation of the cell's functions over time. In other words, senescence, from the Latin senex "old age", is the aging of organisms. From all times, scientists have sought to delay aging in an attempt to respect the Chinese proverb taken up by Malraux

We must add life to years, not years to life.

Several recent studies tend to show that SARS-CoV2 accelerates the biological age of cells. How does it do this? By acting on the size of telomeres, the DNA sequences that protect the end of chromosomes and that shorten with each cell division.

In April 2021, a Chinese study by Yuyang Lei and Jiao Zhang, published on Circulation Research pointed out that the main pathogen of Covid-19 virus is its spike protein, called spike. The spike protein surrounds the viral capsid and allows it to enter cells to infect them. In this study, the researchers isolated Spike by mounting it on an empty nucleus and then inoculated it into guinea pigs to observe its action on the body. The animals developed lung and artery lesions associated with endothelial cell inflammation. The team reproduced the experiment in vitro on healthy human endothelial cells: the spike protein bound to ACE2 receptors, damaging the mitochondria of the cells, causing micro-thrombosis and endothelitis. The conclusions are clear: the Spike protein alone causes most of the symptoms of Covid-19 (Covid in the rest of the article).

A few questions are then burning our lips:

• If it is proven that SARS-CoV2 induces accelerated cellular aging, and that the responsible of this senescence is none other than the Spike protein, how can we be absolutely sure that the vaccines currently on the market, all based on Spike, do not also lead to accelerated degradation of the cells of the vaccinated persons?
• What are the links between the mechanisms involved in telomere shortening-related senescence and vaccines?

Elements of answer can be found in this article. Forewarning to the reader : some paragraphs require some knowledge in biology or biochemistry. The conclusion is for the general public.

Acceleration of biological age

In November 2020, a team of researchers from Cliniques Universitaires Saint-Luc and UC Leuven investigated the potential role of telomeres in Covid infection. Age, obesity, diabetes, hypertension, and many severity factors are now well identified complicating factors. However, patients who do not meet these criteria sometimes suffer severely from this virus.

Telomeres and their role?

A summary article from the same university explains what telomeres are and their role.

• Telomeres are DNA sequences that protect the ends of chromosomes and shorten with each cell division. Their size decreases according to the age of the cell and the individual. When they become too short, especially in the elderly, the cells enter senescence, a phenomenon close to cell death. These structures therefore play the role of a sort of biological cellular clock.
• Many scientists have shown that shortening telomeres reduces life expectancy.
• However, telomere length is not the same for all individuals of the same age and depends, among other things, on certain genetic variants. Telomere shortening seems to affect the body's defenses against viruses and it is assumed that individuals with shorter telomeres deplete their stock of immune cells more quickly.
• In order to better understand the immune mechanisms involved in Covid-19 (almost all patients hospitalized for Covid have a lack of lymphocytes in the blood), Professors Froidure (Respiratory Department) and Decottignies investigated the potential link between telomere size and Covid.
• Researchers compared telomere size in 70 patients hospitalized with Covid during the first wave of the pandemic (between April 7 and May 27, 2020/patients aged 27 to 96 years) to the results of a control group corresponding to approximately 500 non-affected Covid individuals.
• The results showed that i) the telomeres of Covid patients were shorter than those of the reference group and ii) the presence of very short telomeres (below the 10 percentile for age) was associated with a significantly higher risk of ICU admission or death.
• These results open important perspectives in the understanding of the mechanisms of immunity to coronavirus.

Results confirmed and refined in 2021

In January 2021, molecular oncology researcher Maria Blasco confirmed the findings of Froidure et al. published in an unnoticed paper titled "Shorter telomere lengths in patients with severe Covid disease." Bottom line:

• The incidence of severe Covid increases with age, with older patients having the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of Covid. The authors point out that "one mechanism of aging is the progressive shortening of telomeres, which are protective structures at the ends of chromosomes. Extremely short telomeres impair the ability of tissues to regenerate and trigger a loss of tissue homeostasis and disease." The SARS-CoV2 virus infects many different cell types, forcing cell turnover and regeneration to maintain tissue homeostasis.
• The authors therefore hypothesized that the presence of short telomeres in older patients limits the tissue response to SARS-CoV2 infection. They measured telomere length in peripheral blood lymphocytes from Covid patients aged 29 to 85 years and found that shorter telomeres are associated with increased disease severity.

Few articles have reported on these studies except for HealthLog, which coyly titled "What if covid nibbles at telomeres?" before concluding that a question arises: does telomere shortening imply accelerated aging and reduced lifespan?

In May 2021, a pre-publication study (Gorgoulis et al. 2021) concluded that SARS-CoV2 infects lung epithelial cells and induces senescence and an inflammatory response in patients with severe Covid.

In June 2021 the link between telomere shortening in Covid patients and accelerated biological age was proven (Gaetano et al.). The abstract is unequivocal:

• SARS-CoV2 infection results in Covid syndrome, which is characterized, in the worst case, by severe respiratory distress, pulmonary and cardiac fibrosis, release of inflammatory cytokines, and immunosuppression. This condition has resulted in the death of approximately 2.15% of the world's infected population to date.
• Among survivors, the presence of the so-called persistent post-covid syndrome (PPCS) is quite common. In Covid survivors, PPCS is associated with one or more of the following symptoms: fatigue, dyspnea, memory loss, sleep disturbance, and difficulty concentrating. The study measures biological age in 117 Covid survivors and 144 uninfected volunteers.
• The authors find a significant increase in the biological age of patients who had Covid (post-Covid) of 45 years (+/- 7.29 years or 5.25 years beyond the norm) compared to 3.68 years (+/- 8.17 years) in the uninfected (non-covid)

• A significant shortening of telomeres is observed in the post-covid cohort (3.03 kb) compared to the non-covid cohort (10.67 kb).
• In addition, ACE2 expression was decreased by 73% in post-covid patients compared with the non-covid population. This confirms the data from Butwot's May 2020 study of SARS-CoV2, ACE2, and TMPRSS2 entry protein expression in olfactory epithelial cells and the identification of cell types and trends with age.
• In light of these observations, it is hypothesized that certain epigenetic alterations are associated with the post-covid state, particularly in younger patients (<60 years).

Lately, on television or on social networks, many individual testimonies have come to corroborate these facts: thus, it is not uncommon to read, hear or see that a loved one "took ten years" after a severe Covid. But more worryingly, these same impressions are also found in vaccinated people.

What is oxidative stress and what role does it play in telomere shortening and Covid-19?

Chronic (i.e. prolonged) inflammation is ultimately what will cause death in patients with Covid, notably by activating the coagulation phenomenon. This inflammation, which is often called in a simplified way "cytokine storm" or "cytokine storm", is indeed activated by molecules (proteins) called cytokines. These cytokines are like messengers between the cells of the human body that send messages, notably for the regulation of inflammation in the organs.

This inflammation is accompanied by oxidation reactions in the cells by small, highly reactive molecules (called free radicals) that are produced at the site of the inflammation by a process called oxidative stress. It is as if inflammation is the flamethrower and oxidative stress is the flame.

These two closely related phenomena (chronic inflammation and oxidative stress) are at the root of most cardiovascular diseases (atherosclerosis, thrombosis...), neurodegenerative diseases (Alzheimer's, Parkinson's...), cancers, but also aging.

And it turns out that Covid is actually an inflammatory and oxidative disease !

The crucial importance of oxidative stress in Covid pathology has been largely underestimated and should be the subject of further research especially to identify antioxidant/anti-inflammatory treatments (Delgado-Roche L et al., 2020) (Cecchini R et al., 2020) (Ntyonga-Pono MP, 2020); this is also important for the long forms of Covid!

The inflammation triggered by the spike protein in Covid and the associated oxidative stress, involves in particular the dysregulation of the renin angiotensin system and the activation of the bradykinin pathway (Lesgards JF., Cerdan D. 2021, a global vision of the biology of sars).

Numerous works have linked oxidative stress to telomere shortening and thus cell senescence and organism aging (Boonekamp JJ et al., 2017) (von Zglinicki T, 2002) (Kawanishi S and Oikawa, 2004) (Richter T and von Zglinicki T, 2007) (Griffin CS, 2002). Several studies have also demonstrated telomere shortening by adding an oxidant that consumes glutathione (the body's major antioxidant) (Cattan V et al. 2008).

Furthermore, in July 2021, in an unselected patient population hospitalized with Covid, the relationship between oxidative stress and inflammatory biomarkers predicted patient severity and ICU admission (Brack M et al., 2021).

Oxidative stress is responsible for telomere shortening in Covid

In the oxidizing environment of Covid, one of the cellular targets is the bases of DNA and RNA, in particular the bases called Guanines (G). Thus, the main oxidation product found in the body is 8-oxo-7,8-dihydroguanine (8oxoG), which plays a major role in mutagenesis and carcinogenesis, i.e. the induction of cancers (Fortini P et al., 2003). Guanines, if they follow each other in repeated sequences (GG..), are even more easily oxidized (Kino K et al., 2017) which is very present in the genetic sequence of telomeres protecting the ends of chromosomes. Normally the body removes these toxic oxidation products (8oxoG) with an enzyme (OGG1 glycosylase) and repairs the damaged DNA or RNA. But telomeres are very rich in guanine, so they are particularly sensitive to oxidation, and significant manufacture of 8-oxoG shortens telomeres and impairs cell growth (Fouquerel E et al., 2019) (von Zglinicki Tet al., 2000). In addition, telomeres are repaired less efficiently than the rest of the genome, being located at the end of chromosomes (Oikawa S and Kawanishi S, 1999) (Opresko Pl et al, 2005). The presence of these 8-oxoGs reduces the efficiency of telomerase, the enzyme that repairs telomeres, leading to a disruption of telomere length, maintenance and function (Opresko Pl et al, 2005). Alterations due to 8-oxoG not properly repaired can also induce single or double strand breaks (of DNA) leading to overall genomic instability (Coluzzi E et al, 2014).

Numerous works have linked oxidative stress to telomere shortening, promoting cell senescence and aging of the organism (Boonekamp JJ et al., 2017) (von Zglinicki T, 2002) (Kawanishi S and Oikawa, 2004) (Richter T and von Zglinicki T, 2007) (Griffin CS, 2002). Of particular significance are studies directly showing telomere shortening by addition of an oxidant consuming glutathione (the body's major antioxidant) (Cattan V et al. 2008).

This telomere shortening is observed in Covid-19 patients with severe forms, both as an associated risk factor (Froidure A et al., 2021) and as a consequence of the disease. In these patients, there is an increased biological age (reflecting the exact physiological or functional state of the individual) after the disease (Mongelli A et al., 2021). In addition, the plasma concentration of guanine oxidation products (8-oxoG) appears to be associated with mortality (Lorente L et al., 2021).

In other diseases associated with oxidative stress, telomere shortening is also observed; this phenomenon is correlated with age (Harley CB et al., 1990) (Starr JM et al, 2008) and is found in pathologies such as metabolic syndrome (characterized by clinical factors such as obesity, dyslipidemia, hypertension, hyperglycemia and insulin resistance) (Gavia-García G et al., 2021), diabetes (Wang J et al., 2016) (Salpea KD et al., 2010), Parkinson's disease (Watfa G et al., 2011). As can be seen, these are all factors of comorbidities.

Link between senescence and Covid-19 vaccines

Di Fragana et al, in June 2021, describe in a BioRXiv preprint study that this DNA damage (telomere shortening) stimulates SARS-CoV2 ACE2 receptor transcription during aging confirming other studies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is known to be more common in the elderly, who also have more severe symptoms and a higher risk of hospitalization and death. In the study, the authors show that the expression of the enzyme ACE2 (angiotensin-converting enzyme 2), which is the cellular receptor for SARS-CoV2, increases during aging in mouse and human lungs. This is in response to telomere shortening or dysfunction in mammalian cells and in mouse models. This increase is regulated at the transcriptional level and ACE2 activity is dependent on the DNA damage response (DDR).

The authors conclude that during aging, telomere shortening, by triggering DDR activation, causes upregulation of ACE2, the cellular receptor for SARS-CoV2, thus making older people likely more susceptible to infection.

Gueudes' pre-publication work in May 2021, on the comparison of spike RNAs and telomerase (the enzyme that adds telomeres to the end of chromosomes) in SARS-CoV2 that comes to explain the increased aging of alveolar cells in severe COVID-19 cases, provides a link to messenger RNA therapies (used in pseudo mass vaccination) and raises many questions about post-vaccine or post-covid-19 links. Telomerase is a reverse transcriptase and the author offers a comprehensive explanation that requires peer review "The architecture of the telomerase complex involved in telomere (hTR) manufacturing is normally protected from hijacking by foreign RNA and there is a mechanism to control RNA incorporation into telomerase. But when a lot of foreign RNA is present in the cell, telomerase assembly could be impaired."

Recall that in 2003, Scholes et al. in the journal PNAS had already shown that telomere erosion led to the activation of retrotransposons and therefore reverse transcriptase would probably not be necessary to explain that vaccine RNA could interfere with telomerase assembly and disrupt genomic homeostasis.

Is oxidative stress induced by mRNA vaccination (Pfizer, Moderna) also responsible for telomere shortening?

The spike protein in vaccines also induces inflammation and oxidative stress by binding to ACE2 receptors present throughout the body (Lesgards JF, 2021).

Given the severity of the observed side effects and the fact that the biochemical mechanisms are partly similar, it can be hypothesized that mRNA vaccines can oxidize DNA guanines and partly telomeres. It is known that post-vaccine inflammation is produced and sought after to amplify the immune reaction and the production of antibodies, and if we add to this the inflammatory and pro-oxidant action (one does not go without the other), induced by the spike protein and which can last for at least 15 days (Ogata AF et al., 2021), we have an environment that is very conducive to the oxidation of the DNA bases, the most fragile of which is guanine, in particular on the telomers.

Indeed, one study showed that vaccination with the Pfizer vaccine led to an increase in oxidative stress levels (assessed by glutathione measurement) that returned to normal after 14 days (Ntouros PA et al., 2021). This delay was nevertheless sufficient to induce telomere damage.

This oxidative stress produced by vaccination also poses another problem which is the stability of the mRNA of the vaccines themselves! In a very surprising way, the mRNA of Pfizer and Moderna vaccines have been enriched in guanines! This is supposed to increase the translation of RNA into spike protein: indeed, if we study the nucleotide sequence of the spike gene of the SARS-CoV2 virus, and compare it to the coding sequence for the spike protein of the vaccine, we notice many differences which, however, do not affect the translation product (as they are synonymous codons). These changes in the nucleotide sequence were introduced by the researchers to increase the efficiency of the vaccine (they replaced bases with G's, as much as possible, to increase the efficiency of the translation). https://www.pedagogie.ac-nice.fr/svt/?p=2967

But in the same way that it is impossible for manufacturers to ignore the toxicity of the spike protein known for ten years, it is even more impossible to ignore the fragility (oxidizability) of guanines!

It is therefore surprising that none of the regulatory authorities in charge of evaluating the marketing authorization applications for these vaccines (FDA and EMA in particular), knowing the sensitivity of telomeres and DNA to oxidative stress, have requested a toxicity study on genes (genotoxicity).

Extract from the EMA report on Comirnaty (Pfizer vaccine): "Genotoxicity: No genotoxicity studies were provided. This is acceptable because the components present in the vaccine formulation are lipids and RNA which are not expected to have genotoxic potential (EMA, 2021).

This can be considered irresponsible from a scientific and safety point of view.

Are RNA vaccine spike proteins more harmful than the SARS-CoV2 spike protein?

The following three experimental and theoretical explanations allow us to answer in the affirmative. The "apprentice technologists of the living" have thought to make the RNA of vaccines more stable by doping it with G bases, without modifying the corresponding amino acids, which is possible thanks to the "operating mode" of the universal genetic code that allows several triplets of distinct codons to code for one and the same amino acid. Unfortunately, this leads to a diametrically opposite result in the case of vaccine RNAs, as they become more unstable, fragile and brittle.

1 - The article "vaccine-induced Covid-19 mimicry" syndrome (Marschalek et al., 2021) shows how this G-base spiking of spike RNA can generate codon reading frame changes, thus different partial amino acid sequences, which can ultimately lead to thromboembolic events in patients immunized with covid-19 vaccines.

2 - Moreover, it has been demonstrated how this excess of G bases in the RNA of the vaccine spike reduces to zero the megastructures according to the UA/CG proportions defined by Fibonacci, whereas on the contrary, the spike of the virus and especially that of the variants sees the complexity and the quantity of such structures increase. To simplify, this means that the RNA of vaccines is just a stack of nucleotides without any backbone to ensure a megastructure at medium and long distance, while variants acquire more solidity and global cohesion of their RNA day by day (Perez JC 2021).

3 - This inconsistency can also be visualized in the figure below as a kind of "fractal roughness" that is much more unstable and inharmonious in the RNA spike of vaccines (Pfizer specifically) than in the RNA spike of the virus. This was shown using the master code method.

Figure - Erratic Fractal Roughness of Pfizer and Moderna Vaccine Spikes.

Exploratory

On a more exploratory level, research tends to suggest that telomeres and centromeres may also contribute to more global fine-tuning, both at the chromosome level and at the level of the entire human genome.

Indeed, since its initial version in 2003, several successive versions of the entire human genome have been analyzed and published, each one more precise than the last. However, for technical reasons related to their repetitive and very redundant aspect, telomeres and centromeres could not be sequenced in any of these different versions. And it is finally only this year, in 2021, that a version integrating telomeres has been published.

In previous analyses of the 3.5 billion TCAG base pairs of the human genome, two remarkable findings were published:

1 - The first at the scale of the human chromosome suggesting that telomere erosion could affect this global equilibrium at the scale of the whole chromosome: a highlighting of "standing digital waves" resulting from the analysis of the nucleotide sequences of each chromosome (each of the chromosomes is characterized by a period expressed in number of nucleotides, for example 34 for the whole chromosome 4 ( Perez JC. 2018)).

2 - The second at the scale of the entire human genome, where in 2010 it was demonstrated that the populations of codon triplets of the entire human genome, projected according to the positions of each of the 64 codons of the table of the universal genetic code would obey a kind of numerical optimum (Perez JC date ?.). This optimum being more and more refined with the analyses of the more and more precise versions of the human genome (2003, 2005 and...).

In these two articles, it was then demonstrated how deletions in a single chromosome, associated with certain cancers, were sufficient to degrade this optimum balance on the scale of the entire genome.

It is therefore legitimate to think that telomere degradations could also alter this GLOBAL nucleotide balance of the ENTIRE genome in a way similar to that observed in deletions associated with cancers. (See for prostate and breast cancers and for brain cancers glioblastoma and neuroblastoma)

Finally, as previously demonstrated in the case of deletions of chromosome fragments associated with cancer, we believe that this accelerated "erosion" of telomeres, probably linked to the spike protein of the virus but also to the spike of the vaccines, could affect this double equilibrium at the scale of each chromosome and then of the whole genome.

Conclusion

These studies and observations provide key information about the disease and a fundamental answer to the question of the greater susceptibility of elderly or immunocompromised individuals to the disease. Indeed, with aging, telomeres deteriorate and affect cellular reproduction. SARS-CoV2 would lead to an aging of biological age or an acceleration of biological age through increased telomere shortening.

The question that can legitimately be asked is the following: isn't the active spike protein of vaccines (Pfizer, Moderna...) by soliciting/boosting the ACE2 receptor likely to inhibit the beneficial telomere protection function and thus also activate aging?

There would therefore be a direct link between the disease and the human cellular machinery with the intervention of the reverse transcriptase, which is absolutely not the objective of a traditional vaccine.

To fight SARS-COV2, two strategies to be carried out simultaneously seem relevant:

1 - Preventing the disease - with the known therapeutic and medical approach of barrier gestures, early treatment and "proven vaccination". Prevention also involves a healthy lifestyle, a balanced diet, physical activity, sufficient rest and social interaction. Mens sana in corpore sano, the best prerequisite to face viruses and bacteria.

2 - Preventing severe forms of the disease - which requires first of all a complete understanding of the virus, its mode of action and the consequences of the disease on the affected organs.

To date, the health response to the management of the crisis consists of the injection of substances still in trial, still in phase 3 at the time of publication of this article, for which the definition of the word "vaccine" has had to be modified by the WHO itself. Furthermore, it is accepted that injection with messenger RNA technology leads to increased production of the spike protein while not reducing transmission (Pfizer treatment reported to be only 42% effective against the delta variant). This vaccine barrier would also encourage the creation of variants that seek to circumvent it. In countries that have massively vaccinated, data published by the authorities tend to show that a high percentage of hospitalized persons are persons whose vaccination course is complete. It should be noted that to date, French institutions do not report the same observations; this may be explained in part by the delay in the start of the vaccination campaign (+ 2 months compared to Israel for example).

Professor Montagnier states: "to prevent senescence, take antioxidants ! I have been saying this for 30 years, and I would add now : so as not to lose my telomeres".

There are several questions related to the virus:

1 - Is it better to catch the disease in a risky way and develop a natural global immune response or to try the vaccine experiment while incurring the numerous side effects reported by pharmacovigilance, as well as a risk of increased cellular senescence?

2 - Is the deterioration of the biological age the same in Covid patients and in vaccinated patients? Is one worse than the other? At this stage, no one can give a precise answer to these questions.

The fact remains that this virus causes an increase in the biological age of those who contract the disease, the effect of which is probably accentuated by the vaccine injection. With the decrease of the effectiveness on the contamination, it is thus essential to prevent the aggravation of the disease and for that an early management is imperative.

By letting the disease evolve beyond the first days and by using vaccines as the only solution, there is a risk that we will reduce the life span of both adults and children. At a time when women as well as men are trying to age in the best conditions and stay young as late as possible, do we want to take the risk of ruining all these efforts with regular injections? Given the desire to vaccinate children who are not affected by SARS-CoV2, the cure should not be worse than the disease.

Faced with the feelings of certain patients who have contracted Covid and/or certain vaccinated people who testify that they feel as if they have "taken ten years in one go", will science once again provide factual elements of response in favour of early treatment? A final step, which some will not hesitate to take, is to declare that the acceleration of biological age would lead to a decrease in life expectancy.

Authors of the original paper in French in alphabetical order: Xavier Azalbert, Anne-Typhaine Bouthors, Michel Brack, Dominique Cerdan, Walter Chesnut, Gérard Guillaume, Jean-François Lesgards, Luc Montagnier, Jean-Claude Perez. Thanks to the numerous members of the Citizen's Collective for their proofreading.