Never-ageing Anti-aging to cure COVID-19

The coronavirus spreads and the COVID-19 pandemic continues. While serious scientists and clinicians work on designing working therapies, their more creative colleagues pull out some unhinged ideas and run with it to easily excitable media journalists. Some start experimenting on people right away, some got a product to sell, or both.

Low-dose radiation to the lungs may be an effective therapy to reduce inflammation from viral pneumonia like that caused by COVID-19 @NRG_EDU @ANS_org @WHO @iaeaorg @NRCgov @W_Nuclear_News @WorldNuclear @NIH https://t.co/XfwRYYbQFi

— James Conca (@JimConca) May 13, 2020

For example, we all know that high doses of ionising radiation are very harmful, while lower doses are less harmful. Thus, for some scientists it stands to reason that low doses of radiation must be actually beneficial and why not trying that for COVID-19 therapy? Because their hunch is better than scientific evidence or even common sense, some doctors already began irradiating COVID-19 patients based on no science at all. Clinical trials with low dose radiation started in three hospitals in Spain (as reported by Sylvie Coyaud) and at the Winship Cancer Institute of Emory University in USA, as announced by the PI Mohammad Khan on Twitter (and then deleted). The Emory news eventually made it into Forbes, with the headline:

Researchers Explore Low Doses Of Radiation To Treat Severe Coronavirus Cases

Indeed, the idea of a mysterious healing power of low dose radiation is quite old, it was briefly revived in 1986 when Chernobyl went pop, when IARC experts felt those hysterical Ukrainian and Belarussian peasants should actually be grateful for having their health boosted by a healthy dose of gamma rays (read more about their ideas in this book). Hence, who says a crazy theory can’t be revived again, for another disaster?

Another interesting approach to designing COVID-19 therapies is to ask who dies most and then drunkenly fumble your way from there. Around 70% of COVID-19 dead are male, as it happens. This is why on 27 April the New York Times asked:

Can Estrogen and Other Sex Hormones Help Men Survive Covid-19?

The medical logic here is simple. If men are turned into quasi-females with some female hormones, they sure will be protected from the ravages of the coronavirus. It stands to reason, and as NYT announced:

“Last week, doctors on Long Island in New York started treating Covid-19 patients with estrogen in an effort to increase their immune systems, and next week, physicians in Los Angeles will start treating male patients with another hormone that is predominantly found in women, progesterone, which has anti-inflammatory properties and can potentially prevent harmful overreactions of the immune system.”

The clinical trial at Stony Brook in NY has 110 patients and the one at Cedars-Sinai in Los Angeles has 40, in case you thought it all was meant as a joke. Funnily, German doctors associated low testosterone in men with higher COVID-19 mortality, so there. Maybe I should mention that other genius doctors at Cedars-Sinai invented a UV light rod which can be inserted either in the anus or the trachea, to cure bacterial infections, or the coronavirus. Keen to try? Read here.

Nothing is too stupid or embarrassing, because these are COVID-19 times where some nations hit worst have criminal clowns as their leaders. Of course, the biggest COVID-19 risk group are not just men, but old men. Which brings us to the main topic of this article, of the never-ageing anti-aging quackery, repurposed as COVID-19 therapy. It was to be expected, given the insane amount of money anti-aging supplements earn or burn (depending on your perspective).

On 3 May 2020, the British information authority The Daily Mail reported a scientific breakthrough in the fight against the COVID-19 pandemic:

Elderly coronavirus patients should be given anti-ageing drugs to make their immune systems ‘younger’ so they can fight the virus faster, scientists claim

The article referred to a preprint posted by “Harvard scientists”, and its lead author, the Harvard professor David Sinclair is quoted:

“NAD+ is the closest we’ve gotten to a fountain of youth. It’s one of the most important molecules for life to exist, and without it, you’re dead in 30 seconds.“

The idea is genius. Who dies most often from COVID-19? Old people. What to do to escape COVID-19 danger then? Stop being old. How? Buy Professor Sinclair’s anti-aging NAD+ supplements.

If you are still unconvinced: the miraculous anti-aging effect of NAD+ supplementations has been verified by the facts that it appeared in top journals like Cell, the elite Boston of affiliations of the scientists behind it (Sinclair is in Harvard, his postdoctoral mentor Leonard Guarente is at MIT), the massive money invested and made, and the fact that journalistic coverage says it works.

Both Sinclair and Guarente are business heavyweight who made millions. The latter is founder of the anti-aging start-up Elysium, which sells NAD+ supplements patented by Sinclair. But their previous financial masterpiece was the company Sirtis, which was set up by Sinclair to market the magic substance resveratrol as anti-aging supplement. Resveratrol is normally a natural plant substance very popular in with scientists and media, because it is present as trace element in (among many other things) red wine, which makes for excellent marketing.

Resveratrol in a pill would that make you young and on top cure all possible diseases like diabetes and even cancer) via the (never confirmed, but often postulated) process of activation of SIRT enzymes, or sirtuins. These are NAD-dependent deacetylases of various proteins involved in cancer and sensescence, which led Sinclair and Guarente to another commercial idea, namely that of NAD+ as SIRT1 activator, marketable as dietary supplement.

Sinclair sold Sirtis to the pharma giant GlaxoSmithKline (GSK) for $700 million, which made him and Guarente very, very rich. GSK however soon regretted the purchase and abandoned the SIRT research. The snag was hit long before any pharmacological efficiency could be tested in vivo, namely with achieving any significant bio-availability of resveratrol. It is not clear if the lead product SRT501 ever delivered anything. On top of that, one of Sirtris’ original founders Christoph Westphal had to resign when GSK found out he was selling same SRT501 supplements via his own private company. Sirtis then tried its luck with alternative supplements (SRT2104 and SRT1720) but that led nowhere either (there were rumours of toxicity), so GSK pulled the plug completely.

Sinclair of course didn’t give up, among many other businesses he has shares in and advises is the start-up Jupiter Orphan Therapeutics. Which of course sells resveratrol supplements, which of course is now advertised as the cure against COVID-19.

@HeerCollin @FehrLab @MichaelNADbio & I just published https://t.co/lXFYXVLMUj. This is our 1st of several works on #SARSCoV2. We show that the virus upsets the NAD system in powerful & potentially actionable ways /1

— Charles Brenner, PhD (@CharlesMBrenner) April 19, 2020

To give you a bit of perspective: one of Sinclair’s harshest critics is Charles Brenner, professor at University of Iowa. Now Brenner just happens to be chief science advisor of the company ChromaDex, which incidentally just happens to sell a different kind of NAD+ supplements, based on one of his patents. That company just happened to have sued Guarente’s (and Sinclair’s) Elysium over whose NAD+ product is the right one, with Brenner on the frontpage of media reporting (ChromaDex won the lawsuit, I was informed). And guess what: Also Brenner now says NAD+ supplements could prevent you from catching COVID-19, because obviously this is how anti-aging research community ticks.

This very encouraging press release appeared on 20 April:

“ChromaDex Commits to COVID-19 Research[…]

Preclinical research from Dr. Charles Brenner and a team of leading scientists from three US universities concludes that key steps in coronavirus infection and innate immunity involve a tug-of-war with cellular NAD […]

“As a science-based company with a unique NAD boosting molecule and knowing that our cells’ NAD is depleted by viral infections, we take our responsibility seriously and will leverage our science resources to expedite continuing research on the potential impact of Niagen,” says Rob Fried, ChromaDex CEO.”

His thread is based on a paper of ours that is in peer review. You can read it here https://t.co/7bWYxIe8dK — the work is in early days but definitely suggests that higher NAD could promote resistance to establishment of infection. The term for this is innate immunity

— Charles Brenner, PhD (@CharlesMBrenner) May 5, 2020

It is not irrelevant to mention here that Guarente once stood in the middle of a huge research fraud scandal and came out unscathed. His then-postdoc Gizem Donmez falsified a number of high profile papers which won her a professorship at the Tufts University and a very prestigious award from the Ellison Foundation (incidentally, board member then was Guarente). When scientist and whistleblower Paul Brookes exposed Donmez’ Photoshop activities, she hired a star lawyer (who won the David Baltimore case) to threaten Brookes. At the journal Cell, then led by the fraud-fetishist Emilie Marcus, nobody initially gave a toss, the editor tasked with telling Brookes to get lost was Sri Devi Narasimhan, Guarente’s scientific “grandchild”.

Eventually, the fraud proved too much to cover up, all papers were retracted, and Donmez was sacked by Tufts. She returned to Turkey, as faculty member of the Adnan Menderes University. It seems MIT decreed Guarente officially had absolutely nothing at all to do with his own last author’s papers retracted for fraud. Will MIT decide same way in the case of another star scientist now?

Now that we spoke of photoshopping research results, we can return to the discussion of NAD+ discoveries by Guarente’s mentee and business partner, Sinclair. Who is about to save everyone who buys their NAD+ supplements from COVID-19.

Sinclair papers

The following rather recent publication in Cell reported how Sinclair’s proprietary NAD⁺ booster product nicotinamide mononucleotide, marketed commercially to you, the consumer, as NMN pills via authoritative journalism sources, rejuvenates mice.

A Das , GX. Huang , MS. Bonkowski , A Longchamp , C Li , MB. Schultz , LJ Kim , B Osborne , S Joshi , Y Lu , JH Treviño-Villarreal , MJ Kang , T Hung , Brendan Lee , EO. Williams , M Igarashi , JR. Mitchell , LE. Wu , N Turner , Zt Arany , L Guarente , David A. Sinclair Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging Cell (2018) doi: 10.1016/j.cell.2018.02.008

Somehow the loading control from Figure 2 reappeared in Figure S2, only with its labelling flipped and showing a very different tissue. There was more. Somehow samples from different parts of rejuvenated mouse legs became strikingly identical!

Sinclair himself immediately replied on PubPeer in September 2018:

“The authors identified the error immediately after publication and sent a correction to the journal on April 9th, 2018, where it, and the original blots, were vetted. Below is the corrected figure and statement we sent in. We are grateful for the opportunity to rectify the error and apologize for any confusion.”

Cell issued a correction for these figures in February 2019 and closed the case. Another issue, also flagged in September 2018 was disregarded completely, presumably because Professor Sinclair did not agree. Maybe the growth factor VEGF went off and was hence declared to have no effect, equivalent to the empty PBS buffer?

The anti-aging effect of Sinclair’s patented NAD+ pills was certified in a previous Cell paper:

AP. Gomes , NL. Price , AJ.Y. Ling , JJ. Moslehi , MK. Montgomery , L Rajman , JP. White , JS. Teodoro , CD. Wrann , BP. Hubbard , EM. Mercken , CM. Palmeira , R De Cabo , AP. Rolo , N Turner , EL. Bell , DA. Sinclair Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging Cell (2013) doi: 10.1016/j.cell.2013.11.037

That Cell paper from 2013 contains some bizarre compression artefacts which might warrant further scrutiny. Except of course this is Cell, so it won’t. Neither will anyone bother about an even earlier Cell paper by Sinclair:

H Yang , T Yang , JA. Baur , E Perez , T Matsui , JJ. Carmona , DW. Lamming , NC. Souza-Pinto , VA. Bohr , A Rosenzweig , R De Cabo , AA. Sauve , DA. Sinclair Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival Cell (2007)  doi: 10.1016/j.cell.2007.07.035

What happened here? Lanes 3 are mitochondria extracts, prepared with two different mitochondrial extraction protocols. These mitochondria extracts are, as opposed to total cell lysates (lanes 1) and cytosolic extracts (lanes 2), not supposed to contain any Hsp90 protein. Because they probably did anyway, the “mito” lanes of these two gels were edited out and replaced with a blank patch.

Same Figure 5E had a related problem with cell fractionation in Photoshop. Cytosolic extracts in the lane 2 are not supposed to contain any Lamin A/C which is a nuclear protein. But apparently they did anyway, and the advanced technological fix to this cell fragmentation protocol was to paste a blank patch to cover up the problematic protein signal (image on the right).

Ta-da, this is how Harvard scientists produce results for Cell.

In 2013, the Journal of Biological Chemistry corrected a Sinclair paper about NAD+ anti-aging effect, because “the same images of yeast colonies were inadvertently shown for two different wild type controls in Fig. 2A“. Maybe the journal should have another look, there is even more deserving a retraction. To be fair, Sinclair did place an Easter egg by openly anouncing already in the paper’s title about “manipulation”.

RM. Anderson , KJ. Bitterman , JG. Wood , O Medvedik , H Cohen , SS. Lin , JK. Manchester , JI. Gordon , DA. Sinclair Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels Journal of Biological Chemistry (2002) doi: 10.1074/jbc.m111773200

This additional evidence of intentional data fakery in Figures 5B and 3A is 6 years old. Pity Professor Sinclair is too busy getting rich with anti-aging supplements to fix his papers, maybe JBC can help him?

Around 20 years ago, Sinclair was busy extending the lives of yeast, like here in Science:

You might notice that also here, the yeast colony images in Figure 1 were copied with brightness adjusted, so they don’t immediately appear identical. In Figure 3D, yeast colonies cannot be compared with each other because the images were spliced. The paper was never corrected. One does not correct or retract papers from Harvard. Both Cell and Science know it.

There are more vintage Sinclair shenanigans, protocolled by Paul Brookes. The file is available here:

Sinclair is one of the Editors-in-Chief of the journal Aging, next to Mikhail Blagosklonny (who also runs Oncotarget and whose lawyer threatened me to tweet only good thing about this journal). If you wonder how diligent the peer review at Aging is: one of Sinclair’s own papers was submitted and accepted literally over Christmas.

Which brings us to the next anti-aging expert and magic COVID-19 healer, Michael Lisanti, editorial board member of Aging, initially recruited from US to UK as prestigious Muriel Edith Rickman Chair in Breast Oncology at the University of Manchester, then transferred to the neighbouring University of Salford.

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The magazine Heath Europe titled on 8 April 2020:

Could azithromycin prevent NHS workers from developing COVID-19?

Now don’t get overexcited, this is not about Didier Raoult (the miracle doctor from Marseille who designed a chloroquine + azithromycine therapy against COVID-19 (read more here, here. and here). But close.

The article covers the genius idea of Michael Lisanti which is closely related to that of Sinclair’s: rejuvenation to escape COVID-19. At least Lisanti does not offer his own supplements for sale (he was of course more than happy to peddle matcha tea as a cancer cure in return for some cash from OMGtea). What Lisanti usually does, is to propose same boring old drugs like antibiotics or Vitamin C as cancer cures or “senolytics”, meaning Lisanti believes these can dissolve senescent (i.e. aged) cells and rejuvenate you back to your healthy, disease-resistant youth. Coronavirus can’t harm you because you purged all your senescent cells, easy as that.

In a March 30 paper published by Lisanti in his own journal Aging, he declares which drugs exactly:

“two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment.“

No word here about “senolytic” effect of the doxycycline (which is an antibiotic, i.e. it works against bacteria, but not viruses), but Lisanti insisted it inhibits the replication of Dengue virus in vitro, as one paper has shown.

In parallel, Lisanti advocated in The BMJ:

Doxycycline for COVID-19 Prophylaxis in NHS Frontline Workers

Lisanti wrote there:

“I would like to propose that frontline NHS healthcare workers take the antibiotic Doxycycline (1) prophylactically to prevent COVID-19 infections in hospital and GP settings nationwide. For example, they could take 100-mg of Doxycycline per day.“

FA. Medina , CJ. De Almeida , E Dew , J Li , G Bonuccelli , TM. Williams , AW. Cohen , RG. Pestell , PG. Frank , HB. Tanowitz , MP. Lisanti Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during Salmonella enterica serovar Typhimurium infection Infection and Immunity (2006) doi: 10.1128/iai.00949-06

Do you see the two bands most obviously erased in Photoshop for “Cav-1 KO” samples? Now, as the paper’s title says, this is about Caveolin-1 deficient mice, obtained by genetically knocking-out (KO) a gene, here Cav-1. The KO mice were supposed to show no signal for Cav-1, but they apparently did very much, hence the Photoshop job. Does this change the conclusions of the paper that Cav-1 KO mice were actually not gene deficient at all? The journal, published by American Society for Microbiology (ASM), thinks it doesn’t. The paper was not just not retracted, nothing at all happened despite the now 6 year old public evidence.

Lisanti’s expertise, when he is not curing cancer and COVID-19 with antibiotics, is in the endocytosis and the relevant membrane protein caveolin, and this again is how he achieves the results:

Babak Razani, Michael P. Lisanti Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A AJP Cell Physiology (2001) doi: 10.1152/ajpcell.2001.281.4.c1241 

The two Phospho-CREB bands appear suspiciously similar. But the publisher American Physiological Society saw no reason to have a closer look. Noteworthy, this paper has only two authors, difficult to shift the blame to Lisanti’s collaborators at Albert Einstein College of Medicine, Richard Pestell , and definitely not upon Herbert Tanowitz , now deceased.

More of that, maybe?

Jasmin JF, Mercier I, Hnasko R, Cheung MW, Tanowitz HB, Dupuis J, Lisanti MP. Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression. Cardiovasc Res. 2004 DOI: 10.1016/j.cardiores.2004.05.018

Just some copy-pasted gels bands apparently, quality science made at Einstein Medicine in New York.

Update 18.06.2020. Guess what the Editorial Office of Cardiovascular Research decided in this case:

“We have asked  two independent reviewers to conduct in-depth image analysis and they have concluded that there is no evidence of data tampering. This was also reviewed by the ESC Journal Family Ethics Committee who agree with their findings. We have deemed that no correction is needed.“

Lisanti once did earn a retraction, but for a different paper, Schlegel & Lisanti J Cell Physiology 2001. The retraction notice went:

“The Publisher regrets that this review article must be withdrawn owing to an issue of multiple publication. The manuscript was submitted in nearly identical form to three journals (Frontiers in Bioscience, Cytokine and Growth Factor Reviews and Journal of Cellular Physiology) and was accepted and published by all three. As the article was accepted and published in Frontiers in Bioscience first, the copyright belongs to that journal.”

Seriously, what kind of lab does Lisanti run, where things like that happen? Finally, a vintage Lisanti, and there is more on PubPeer.

F. Galbiati , D Volonte , J A Engelman , G Watanabe , R Burk , R G Pestell, M P Lisanti Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade The EMBO Journal (1998) doi: 10.1093/emboj/17.22.6633

Whatever that is, it is not science. It is trolling, and it doesn’t matter that it happened long before the word was invented.

Media-savvy scientists like Lisanti, Guarente and Sinclair, and of course also Didier Raoult, are celebrated in the newspapers and on TV almost on weekly basis, each crazy claim of theirs makes national and international news because the solutions they offer are so simple, straightforward and magical. Nobody cares about how they actually do their science. Data manipulations? Pah. Debunked and irreproducible? Ignore their envious detractors.

@schneiderleonid El #GobiernoCriminal financia al defraudador científico Otín, pero es que es de los suyos…
El Instituto Carlos III financiará un proyecto de López-Otín y López Soto sobre el coronavirus https://t.co/lifQIe6M96 vía @elcomerciodigit

— Día Día (@ddia7940) May 14, 2020

Spanish government and science elites seem to feel they need to out-fraud the Americans and the French. The first ever COVID-19 research grant from the Ministry of Science and Innovation was awarded to… no seriously, it is not a joke: Carlos Lopez-Otin. A zombie scientist who even admitted data forgery, with 9 retractions and revoked Nature award, killer of over 5000 rodent witnesses, and a laughing stock of the entire scientific community outside of Spain. Incidentally, the national martyr St Carlos of Oviedo is also an anti-aging researcher, and yes, this is also what his COVID-19 approach will be about.

Now we are supposed to follow these alpha men’s (they are all men, incidentally) guidance on COVID-19 therapies. The journalists are convinced, the patients believe what scientists tell them in newspapers and run for bullshit cures. For proper, scientifically supported clinical trials, there is hardly anyone left to participate, and how does one do drug discovery for COVID-19 then?

Oh who cares, here is the sodding Robert Gallo himself with solutions to coronavirus vaccine and COVID-19. On BBC.

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