I'd like to counter some weird obfuscation that appeared today /1
in 2004, Pawel Bieganowski and I were 1st to describe the NR kinase pathway to NAD+, which--along with 3 related coenzymes--is the central catalyst of metabolism in all forms of life /3
I don't call myself a longevity scientist. I consider the category of "anti-aging" to have a remarkable track record of non evidence-based wishful thinking and deceit. My lab does NAD, all day, every day in health and disease /4
@dartmouth patented my inventions on uses of NR in nutritional (food & supplement) and drug applications. 10 yrs ago @ChromaDex exclusively licensed these patents, developed a proprietary manufacturing process, worked with @WRGrace to crystallize NR chloride /5
Further, they did animal testing, we've done human testing, which has resulted in new dietary ingredient & GRAS notifications from @US_FDA plus similar notifications in multiple countries around the world /6
This material, which we've shown to be safe & orally effective at elevating the human NAD metabolome in multiple human trial, is trade named Niagen as an ingredient & available from @truniagen as a finished product /7
I'm the chief scientific advisor @ChromaDex. I don't run marketing or advertising for them. I do help them understand the science & guide research. There are places on the internet where it's said that scientists @MIT or @Harvard developed this technology, though /8
In 2010 & more definitively in 2013, we described methods for quantitative targeted NAD metabolomics, which has allowed us to discover that the central catalysts of metabolism are not stable to conditions of metabolic stress /9
In papers too numerous to tweet, we & others have shown that noise-induced hearing loss, overfeeding, alcoholic liver disease, DNA damage, heart failure, peripheral & central neurodegeneration, postpartum, inflammation & coronavirus infection disturb one or more NAD coenzymes /10
Generally, the NAD metabolome deficit is centered on either NAD+ or NADPH & results in a bioenergetic crisis, failure to repair DNA, failure to detoxify reactive oxygen species &/or other operational failures that cause tissue damage /11
I truly don't know what it means when ppl say that NAD+ declines in aging. In what tissue? What was the method used to show this? NAD coenzymes do come under attack in conditions that are virtually unavoidable (think sun & oxygen) /12
The innate immune system & chronic inflammation disturb the NAD system but this is not driven by time but rather episodes. A cat handler has more scratches on her hands over time but the scratches were caused by cats, not time /13
Metabolic processes (including ATP generation, anabolism and repair) clearly decline in aging. Many of these have an NAD component to them. Without hype, our lab tries to determine what specifically is happening. If NAD+ or NADPH is in decline while NR kinase genes are up /14
there is a very good chance that NR will be protective. We've shown this to be the case in animal models of fatty liver, diabetic & chemotherapeutic neuropathy, heart failure, & postpartum (the mother of all metabolic stresses) /15
we've used these results to design & help others design clinical trials to see improved resiliency in important human conditions. initial results show excellent safety & oral availability & suggest we should combine NR w exercise in future trials doi.org/10.1093/ajcn/n… /16
So what was the work @MIT & @Harvard & how is related to NR? Is my work derivative of someone else's? /17
Yeast cells can be used to study aging, though they divide every 90', don't differentiate into complex tissues, & become inviable over the course of days or weeks /18
@davidasinclair & Leonard Guarente showed that in the replicative model of aging, extra copies of SIR2 gene confer a longer lifespan. @mkaeberlein however showed that this is not true in all yeast strains /19
Moreover, Valter Longo showed that deleting SIR2 extends chronological lifespan in yeast cell.com/fulltext/S0092…, thereby showing that SIR2 is not the key mediator of lifespan even in yeast /20
While extra copies of SIR2 were initially reported to extend lifespan in flies & worms, investigators from 9 top institutions could not reproduce these results, undermining the idea that SIR2-related genes promote longevity ncbi.nlm.nih.gov/pmc/articles/P… /21
Prior to the debunking of SIRT genes as longevity genes, the yeast-worm-fly results seemed plausible. @BelenkyLab & I showed in 2007 that NR could extend lifespan & increase SIR2 activity in yeast pubmed.ncbi.nlm.nih.gov/17482543/ 22
We never overinterpreted or overgeneralized our results. @davidasinclair's company Sirtris held a license to one of my NR patents but instead developed resveratrol & other compounds they claimed were direct activators of SIRT1 /23
As a member of the Sirtris SAB, I was never shown convincing data that any SRT compound has a specific, stimulatory reaction on any sirtuin. It can't be true that resveratrol could be active on yeast SIR2 pubmed.ncbi.nlm.nih.gov/12939617 /24
if a unique, human SIRT1-specific amino acid mediates the binding of resveratrol ncbi.nlm.nih.gov/pmc/articles/P… /25
In fact, the resveratrol assay was convincingly shown to be an artifact pubmed.ncbi.nlm.nih.gov/15749705 /26
& ppl frequently need reminders that resveratrol is polyphenolic compound that binds scores of different proteins, that Sirtris compounds & resveratrol neither bind SIRT1 nor increase mitochondrial capacity in mice pubmed.ncbi.nlm.nih.gov/20061378 /27
The insiders at Sirtris, however, sold these compounds & this research program to @GSK for $720 m. Imagine how they felt when the fly, worm, mouse & chemical data they were sold were shown to be deeply flawed & irreproducible xconomy.com/boston/2013/03… /28
More than a decade after resveratrol was debunked as a SIRT activator & SIRT1 was debunked as an anti-aging gene, there are still ppl pushing this story. Truly it is a cult, which means that there are a few leaders of the cult /29
& a large number of ppl under its influence without realizing they are under its influence /30
The leaders of the sirtuin cult have something in common. Their reputations have been staked on 1 or more SIRT-related genes being "anti-aging." They are also often linked to resveratrol & related compounds being SIRT activators /31
They are highly influential, highly cited & have trained a large number of ppl in science. Not only do journal editors expect to see linkages between these genes & aging, the general public does as well /32
Thus, for example, when @Auwerx_Lab & @carlescanto did the first NR experiment showing that mice fed a high fat diet resisted weight gain when supplemented with NR, they showed that SIRT1 & SIRT3 activities were increased pubmed.ncbi.nlm.nih.gov/22682224 /33
At no time have they or anyone else shown that SIRT1 or SIRT3 mediate the beneficial effects of NR in this model and, in fact, we showed that the epicenter of disregulation in the high fat-fed mouse is its liver NADPH pubmed.ncbi.nlm.nih.gov/27230286 /34
When we launched @truniagen, @sclips & I agreed that we had our work cut out to clarify the science around NAD. Age contributes to & complicates all conditions of metabolic stress. By boosting NAD-dependent processes, NR promotes resiliency in animals & is clearly safe in ppl /35
I agreed to Age Better as a trademark. I understand that when trying to communicate NR in fewer than 40 tweets, we need pithy phrases. However, the ideas that aging is optional, reversible, understood, or primarily due to inactions of sirtuins are not evidence-based at all /36
Back to the cult of the sirtuins. The cult followers are mostly not at fault. It is easy to show that when the NAD metabolome is increased, that SIRT proteins have higher activities. This is correlative but not an experiment that probes the significance of SIRT activities /37
Another company initially had my patents on the label of their NR product and to this day claims that their product, containing a resveratrol analog and NR was "developed by an MIT scientist." Remarkable. /38
Obviously, my work was not derivative of theirs & their clinging to the sirtuin narrative is remarkably devoid of scientific substance /39
What about NMN? NMN is NR with a phosphate put on it. Two enzymes in cells produce NMN, namely the NR kinases that we described, and NAMPT, which is kind of Shin-ichiro Imai's baby. NMN is exclusively formed inside cells. No one has ever shown formation of NMN outside cells /40
Compounds with phosphates can't get into cells. That's why the mRNA vaccines were in lipid nanoparticles & cancer drugs that act as nucleotides are given to patients either as nucleosides (similar to NR) or with chemistry that "masks" the phosphate /41
Precisely because NMN won't go into cells intact (shown by @carlescanto, myself & others) pubmed.ncbi.nlm.nih.gov/27725675, /42
@davidasinclair's company Metro Biotech synthesized NMN derivatives that will get into cells patents.justia.com/patent/2020035… /43
Here's the crux of the problem: NR is a remarkable compound with amazing activities in mice & rats. We know that Niagen is safe bc we tested it but we can't vouch for NR produced by copycats, especially if they add a molecule that raises LDL-C in ppl doi.org/10.1016/j.clnu… /44
While we & others do clinical trials against COVID, mild cognitive impairment, neuropathy & other indications, we know that ppl with bigger microphones have claimed to solve the aging problem with NMN. The data are consistent with NMN delivering NR but /45
The idea that NMN is closer to NAD than NR because the phosphate is on is dumb bc the phosphate has to come off, the NMN ppl are taking has little to no safety dossier, & the SIRT-centric mechanisms are fantastical and misleading just like the resveratrol ripoff /46
I do think that NR or a compound that delivers NR could find medical uses after sufficient testing. But the compound won't be modified NMN. Reason being that when NMN accumulates in cells, it kills them doi.org/10.1016/j.neur… /47
Regular NMN won't have this problem bc it can't get into cells but modified NMN is toxic. So I expect the Metro Biotech business plan to change to getting rid of sick cells rather than making longevity claims if they want to use masked NMN ncbi.nlm.nih.gov/pmc/articles/P… /end
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