The COVID-19 pandemic is soon over, a cure is found. It’s of course the senolytics. Because every scientifically literate person knows that COVID-19 is a disease of old age, i.e. cellular senescence.
Senolytics are the therapeutic solution targetting a problem which some may doubt even exists. Cellular senescence is an interesting cell culture phenomenon, where cells stop dividing, grow in size, develop vacuoles and express a certain enzyme, senescence-associated beta-galactosidase. Yet it is not exactly clear how biologically relevant this cell culture phenomenon is. The scientific theory, established in all the top journals like Nature, Cell and Science, is that those senescent cells are the root of all evil, and cause all possible diseases, not just of old age. Alzheimer’s, arthritis, cancer even, and now somehow also COVID-19.
The idea is: all you have to do to cure those diseases is to remove the evil senescent cells, i.e. to dissolve them with senolytics. Pharmacologically, senolytics are drugs which are deemed to be inhibitors of various proteins related to cell cycle control and cell survival. Problem is that too often the same scientists who make the groundbreaking discoveries about senolytics and the dangers of cellular senescence are also active businesspeople seeking to monetize their research papers. They found their own biotech startups, or sit on the board of pharma giants.
But not Clemens A Schmitt of the Max Delbrück Center and the Charité University Medicine in Berlin, Germany. Professor Schmitt, who since 2018 has another professorship at the Johannes Kepler University in Linz, Austria, has no conflicts of interests whatsoever, as nearly every single one of his papers proudly declares. And now Professor Schmitt found the cause and the cure for COVID-19.
Here is his new paper in Nature, the first author is Schmitt’s long-term collaborator and sub-group leader at Charité, Soyoung Lee. It is a hot candidate for the Nobel Prize:
Soyoung Lee , Yong Yu , Jakob Trimpert , Fahad Benthani , Mario Mairhofer , Paulina Richter-Pechanska , Emanuel Wyler , Dimitri Belenki , Sabine Kaltenbrunner , Maria Pammer , Lea Kausche , Theresa C. Firsching , Kristina Dietert , Michael Schotsaert , Carles Martínez-Romero , Gagandeep Singh , Séverine Kunz , Daniela Niemeyer , Riad Ghanem , Helmut J. F. Salzer , Christian Paar, Michael Mülleder, Melissa Uccellini, Edward G. Michaelis, Amjad Khan, Andrea Lau, Martin Schönlein, Anna Habringer, Josef Tomasits, Julia M. Adler, Susanne Kimeswenger, Achim D. Gruber, Wolfram Hoetzenecker, Herta Steinkellner, Bettina Purfürst, Reinhard Motz, Francesco Di Pierro, Bernd Lamprecht, Nikolaus Osterrieder, Markus Landthaler, Christian Drosten, Adolfo García-Sastre, Rupert Langer, Markus Ralser, Roland Eils, Maurice Reimann, Dorothy N. Y. Fan, Clemens A. Schmitt Virus-induced senescence is driver and therapeutic target in COVID-19 Nature (2021) doi: 10.1038/s41586-021-03995-1
The study reports the discovery of virus-induced cellular senescence, treatable with senolytics, as per abstract:
“Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-191–4. Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and accompanied by a senescence-associated secretory phenotype (SASP), composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators5–7. COVID-19 patients displayed markers of senescence in their airway mucosa in situ and elevated serum levels of SASP factors. […] Senolytics such as Navitoclax and Dasatinib/Quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-driven hamster and mouse models. Our findings mark VIS as pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest senolytic targeting of virus-infected cells as a novel treatment option against SARS-CoV-2 and perhaps other viral infections.”
Also Germany’s star of COVID-19 research and Charité’s professor of virology, Christian Drosten, is on board as co-author, which gives the study an undisputable final authority. But then again, Drosten seems to be too polite to refuse an invitation to join a paper in a top journal. This is why he also declared in February 2020 in The Lancet (Calisher et al 2020) that all discussions about possible lab origins of COVID-19 are “conspiracy theories”, while saying something else in his more recent interviews.
Here is the institutional press release by the Charité:
“A team of researchers from Charité – Universitätsmedizin Berlin, the Max-Delbrück-Center for Molecular Medicine (MDC), Johannes Kepler University (JKU) Linz and Kepler University Hospital (KUK) led by the oncologist Professor Clemens Schmitt has now shown in “Nature“ that this process plays a crucial role in triggering a veritable avalanche of inflammatory mediators, which contribute to the lung damage associated with COVID-19. Drugs capable of selectively eliminating senescent cells were shown to mitigate COVID-19-related lung damage in animal models, in addition to significantly reducing inflammation. “In our view, the early use of specific substances which disrupt this inflammatory overreaction holds enormous potential as a new treatment strategy for COVID-19,” says the cancer specialist.”
Schmitt is quoted:
And his collaborator Lee adds is certain that senolytics are the solution to many other infectious diseases:
Thus, another stellar team of professors joined the fight on the cytokine storm front. This time, with senolytics.
Let us look closer which senolytics solutions the Charité team around Lee and Schmitt proposes. Their favourite, Navitoclax, is described as an inhibitor of Bcl-2, an anti-apoptotic gene. The drug is the first-generation Bcl-2 inhibitor and was already establish as a cure for Alzheimer’s (in mouse model) by a certain Mayo Clinic lab (Bussian et al Nature 2018). The other drug is Dasatinib, a tyrosine-kinase inhibitor used for leukaemia chemotherapy, its common side effects are “infection, suppression of the bone marrow (decreasing numbers of leukocytes, erythrocytes, and thrombocytes), headache, hemorrhage (bleeding), pleural effusion (fluid around the lungs), dyspnea (difficulty breathing)…” Hence perfect for COVID-19 pneumonia or did I miss something?
But according to this study by Schmitt lab, a similar senolytics effect can be also achieved by the dietary supplements Fisetin and Quercetin (ubiquitous plant flavonoids, also widely available to buy as prescription-free, overpriced and utterly useless supplements). This neatly fits to the previous discovery by other Charité scientists, namely professors Torsten Zuberbier and Jean Bousquet who postulated that Quercetin and other substances in fresh and fermented vegetables can cure COVID-19:
Senolytics for Cancer
When all you have is a hammer everything starts looking like a nail. This is apparently also true when your hammer is senolytics. Schmitt, as per self-description, aims “to exploit the anti-cancer potential of selectively senescent cells-eliminating “senolytic” therapies”, and he does so for over two decades already. In two other Nature papers (Dörr et al 2013, Milanovic et al 2017), Schmitt and Lee postulated that chemotherapies with anti-proliferative drugs actually drive cancer by inducing senescence of cancer cells, which then somehow turns those into highly aggressive cancer stem cells. Basically, senolytics are the only way to treat cancer and COVID-19, time to follow the science, pardon, Nature.
The current paper in Nature, on senolytics for COVID-19, declares these conflicts of interest:
“M.U. [Melissa Uccellini] contributed to this article as an employee of Mount Sinai and the views expressed do not necessarily represent the views of Regeneron Pharmaceuticals Inc. F.D.P. [Francesco Di Pierro] is a member of the Scientific Board of Pharmextracta S.p.A., the vendor of Quevir®, a dietary supplement containing Quercetin in a sunflower lecithin formulation. The A.G.-S. [Adolfo García-Sastre] laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak and Pfizer. A.G.-S. is inventor on patents and
patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by the Icahn School of Medicine at Mount Sinai, New York.“
Schmitt, as you may notice, is simply silent. Similar thing happened in the recent position paper Prasanna et al 2021, authored by all the big players in the senolytics field, titled “Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy“, which promoted a ” “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of” senescent cells. While other authors listed their start-up companies, pharma gigs and patents, Schmitt didn’t say anything. This is supposed to insinuate that Schmitt has no financial conflicts of interests (COI) to declare. When I asked him to share with me a list of his patents and sources of pharma remuneration, Schmitt told me to search “as usual in the Nature publications, in the “Competing Interests” section“.
But I did find some papers by Schmitt where he did declare a COI. In one of them (Schmitt 2020), he stated:
“C.A. Schmitt declares the following conflict of interests pertaining to this manuscript: Roche: Advisory board and speaker’s honoraria; Janssen-Cilag: Speaker’s honoraria and clinical trial/research support.”
Now, a certain company named Genentech just began marketing together with another pharma company, Abbvie, the drug Venclexta (Venetoclax). That one is actually a next generation derivative of Navitoclax, supposedly more specific for Bcl-2. And Genentech is a branch of Roche, whose advisory board Schmitt sits on. So already this small bit of information I found by online search does sound like a heavy financial COI for a certain Charité professor who declares Navitoclax to be the therapy for COVID-19.
Schmitt promised to send me a list of his patents and pharma involvements, but mentioned that “it will take some time“.
Conclusions not affected
Possibly not related, but I thought I’ll mention it anyway: a corrected paper. In 2020, Schmitt, accompanied by two of his lab members at Charité, published a study on the topic of senolytics therapy with a certain senescence researcher, Oliver Bischof:
Ricardo Iván Martínez-Zamudio, Pierre-François Roux, José Américo N.L.F. De Freitas , Lucas Robinson , Gregory Doré, Bin Sun , Dimitri Belenki , Maja Milanovic, Utz Herbig, Clemens A. Schmitt, Jesús Gil, Oliver Bischof AP-1 imprints a reversible transcriptional programme of senescent cells Nature Cell Biology (2020) doi: 10.1038/s41556-020-0529-5
The paper contained what looked like duplicated data:
In June 2020, the paper was corrected, listing all these “errors” of “inadvertently copied” data. Which probably means the paper is now 100% reliable and no conclusions were affected in the making of that correction. Soon after, 4 papers by Oliver Bischof were retracted, he was found guilty of research misconduct and dismissed by his French employer, the Institut Pasteur, as its scientific director informed me:
“The evidence and conclusions indicate that during the preparation of many of the publications O. Bischof […] had engaged in fraudulent practices, in violation of the rules of honesty and scientific integrity. After due consultation with the President of the CNRS, Prof Cole, President of the Institut Pasteur, asked O. Bischof to leave the Institut Pasteur without delay.“
Update: Schmitt explained me how the correction of the above paper is to be understood:
“It goes without saying that Oliver Bischof’s scientific misconduct prompted us to examine the said co-authorized NCB publication particularly critically; From our point of view, there are no recognizable criticisms here. Since you, like me, are concerned about “Better Science”, it is certainly important with regard to the findings presented there that later in 2020 very similar evidence was reported in a Nucleic Acids Research Paper by another group of authors (Guan-Y et al.)“
I presume it was that paper, Guan et al 2020. It does not reference any papers by Bischof, and mentioned activator protein 1 (AP-1) only once, in passing: “The CTF and bZIP (AP-1) family motifs displayed no enrichment preference for SAEs [senescence-activated enhancers] or SIAEs [senescence-activated enhancers]”, while Schmitt’s paper with Bischof declared as its central finding: “We demonstrate that activator protein 1 (AP-1) ‘pioneers’ the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells.“
Conclusions not affected.
But of course it is not just Schmitt and Nature who say senolytics are the solution to this pandemic.
Science, as in Science, has spoken:
Christina D. Camell, Matthew J. Yousefzadeh, Yi Zhu, Larissa G. P. Langhi Prata, Matthew A. Huggins, Mark Pierson, Lei Zhang, Ryan D. O’Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi , Jair Machado Espindola-Netto , Nino Giorgadze , Elizabeth J. Atkinson , Christina L. Inman , Kurt O. Johnson , Stephanie H. Cholensky , Timothy W. Carlson , Nathan K. LeBrasseur, Sundeep Khosla, M. Gerard O’Sullivan, David B. Allison, Stephen C. Jameson, Alexander Meves, Ming Li, Y. S. Prakash, Sergio E. Chiarella, Sara E. Hamilton, Tamara Tchkonia, Laura J. Niedernhofer, James L. Kirkland, Paul D. Robbins Senolytics reduce coronavirus-related mortality in old mice Science (2021) doi: 10.1126/science.abe4832
The scientists, or rather the business people of the Mayo Clinic (James L. Kirkland) and the University of Minnesota (Laura Niedernhofer and Paul Robbins), have found a solution to COVID-19 which is different from Schmitt’s virus-induced senescence, according to this press release:
“Based on the “Amplifier/Rheostat Hypothesis” of senescent cells developed at Mayo, the researchers sought to discover how COVID-19 causes much higher mortality in the elderly and chronically-ill. They showed that human senescent cells have an amplified response to the SARS spike protein, provoking increased production of factors causing inflammation and tissue damage by senescent cells.”
But the therapy is the same! The Rochester geniuses discovered that you can prevent severe COVID-19 by killing those virus-attracting old cells of yours with
We are informed that “Three such clinical trials are now underway.“
Now if you want to survive COVID-19 and are not a fan of vaccines, you must buy the fisetin supplement. Or join one of Professor Kirkland’s three clinical trials sponsored by the Mayo Clinic: NCT04476953, NCT04771611 or NCT04537299. Which will extend your life as a welcome side effect!
Because 3 years ago, same scientists discovered that “Fisetin is a senotherapeutic that extends health and lifespan“, and published it as Yousefzadeh et al EBioMedicine 2018.
The lead authors Niedernhofer and Robbins declare to be, among other things, “co-founders of NRTK Biosciences, a startup focused on the development of novel senolytics“, fisetin in particular. Robbins is also “co-founder and member of the Scientific Advisory Board for Genascence Corporation, a gene therapy company focused on osteoarthritis.” Kirkland is “a member of the Scientific Advisory Board for Elysium Health, marketing dietary supplements“. Yes, same Elysium NAD+ supplement-peddling
scam business owned by Leonard Guarente of MIT and David Sinclair of Harvard:
And here is Sinclair himself, all excited about getting even richer than he already is:
Senolytics are a tempting business model, and one can use peer-reviewed papers in Nature journals as a cheap yet highly efficient way of advertising for your business.
Like recently a bunch of Soviet emigrees, all male, all affiliated with the anti-aging company Gero in Singapore (developing a kind of senolytics, and run entirely by people with Russian names). They published a
company advertisement research paper Pyrkov et al Nature Communications 2021 which made big news: Humans can live till 150, and Gero is “Hacking Aging” to sell you the method!
Knee arthritis is a popular field for senolytics also, simply because there are oodles of patients, approvals are relatively easy to get since the knee is not a vital organ, and with some luck, there will be enough placebo effect to claim success. The Salk Institute genius Juan Carlos Izpisua Belmonte had some preclinical collaborations with a knee therapy clinic in Spain in this regard:
The biggest pratfall with senolytics was by Unity Biotechnology, also with knee arthritis.
“The company, based out of Brisbane, California, has received more than $300 million in funding, including from $85 million raised after going public this past May. Amazon founder Jeff Bezos and PayPal co-founder Peter Thiel are also investors. today the company’s market cap is $700 million.“
One of Unity’s flagship senolytics was UBX0101, which was actually a made-up name for the patent-less substance Nutlin 3a, a p53/MDM2 interaction inhibitor, which is purported to induce apoptosis in those cells which express the senescence marker gene p16, as a Nature News article hinted.
Nutlins have been proposed as cancer therapy drugs by many enterprising researchers, but apparently that led nowhere. Obviously Unity could not patent the molecule Nutlin-3a, which other people (Vassilev et al 2004) have years before discovered to be an MDM2 antagonist. But what Unity could patent, was the use of Nutlin-3a against specific diseases. Knee arthritis, for example. It looked so promising:
“We have spent the last four years identifying a series of Achilles heels that are unique to senescent cells,” says Unity CEO Nathaniel David. “We have molecules that are 300 times more poisonous to these cells than to non-senescent ones.”
“Last year, Unity posted phase 1 data linking UBX0101 to improved scores on pain symptom questionnaires in patients with moderate to severe osteoarthritis (OA), but the drug failed to statistically outperform placebo in the second part of the study.
Unity, however, ploughed on, seeing enough promise in the data to move the p53/MDM2 interaction inhibitor into phase 2. Unity recently completed enrollment in the 183-subject trial, setting it up to post top-line data in the second half of the year.”
On 17 August 2020, Unity Biotech issued this press release, referring to the aforementioned phase 2 clinical trial NCT04129944 on 183 patients with moderate-to-severe painful osteoarthritis (OA) of the knee:
UBX0101 failed to meet 12-week primary endpoint
“There was no statistically significant difference between any arm of UBX0101 and placebo at the 12-week endpoint for change from baseline in WOMAC-A, an established measurement of pain in OA. Given these results, UNITY does not anticipate progressing UBX0101 into pivotal studies and will narrow the company’s near-term focus to its ongoing ophthalmologic and neurologic disease programs. […]
There were no treatment-related serious AEs and only one patient discontinued because of an AE (for an unrelated cardiovascular event). The most common treatment emergent AE was procedural pain in the study knee (n = 10/183 (5.5%)). […]
Anirvan Ghosh, Ph.D., chief executive officer of UNITY. “While these are not the results we had hoped for, the evidence that senescent cells contribute to diseases of aging remains compelling, and we are excited to advance UBX1325 for retinal diseases, which inhibits Bcl-xL, a distinct senolytic target.”
So now Unity abandoned one senolytic and turned to another, the mysterious
Some reasonably argue that “UBX1325 may even be a modified version of Navitoclax.” Which, as Professor Schmitt tells us, is the miracle drug against COVID-19. Senolytics work against everything, you see.
Some of the content was already published in Schneider Shorts
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