Thread by @CharlesMBrenner

in 1997 David was a postdoc with Lenny Guarente & published a very nice paper showing that SIR2 extends the number of times a yeast mother cell can produce daughter cells by controlling formation of ribosomal DNA circles doi.org/10.1016/S0092-…

https://twitter.com/heyitsmebrandon/status/1492517314860060672

David knew then that rDNA circles don't exist in other organisms & he knew that there are extremely few old mothers in a culture. Here's a quote from the paper "50% have no bud scars, 25% have 1, 12.5% have 2, etc. Among 100 cells counted, no cells had greater than 6 bud scars."

The longevity phenotype David was explaining is how a yeast mother cell, who has already produced daughters 20 times, can produce daughters another 10 times or more. By David's own calculation, this old mother is an extremely rare cell: 1 in 2 to the 21st power!

You can regenerate the yeast culture with any single cell. You can't find old mothers & you don't need them. There's no selective pressure on the function that David was describing. The 1997 paper responsibly didn't overstate the generality of SIR2.

David & Lenny reasoned that the SIR2 system depends on asymmetrical cell division & repression of DNA circle formation & suggested that if formation of DNA circles is involved in other types of aging, that perhaps it could be inhibited.

Something strange happened next. David & Lenny disagreed on the mechanism regulating SIR2: DS claimed that NAM inhibits SIR2 while LG claimed that NADH inhibits SIR2. Both mechanisms are wrong: at high glucose, SIR2 is not inhibited by either NAM or NADH pubmed.ncbi.nlm.nih.gov/20175898/

However, over several years, DS & LG propagated through review articles, popular press interviews & public talks the idea that they had found the central regulator aging: the mediator of the benefit of calorie restriction. They each started a company to exploit this idea.

This was a remarkable stretch: the yeast phenotype occurs in 1 dispensible cell out of of 2^21st power of cells! Animals don't have ribosomal DNA arrays that form circles. Better yet, yeast sir2 deletion mutants live longer when calorie restricted cell.com/fulltext/S0092…

and even in the replicative lifespan model affecting the rare old mothers used by LG & DS, SIR2 does not mediate the calorie restriction effect on yeast lifespan as a general phenomenon journals.plos.org/plosbiology/ar… --the papers showing that SIR2 is not the central yeast longevity gene

were published by major researchers: Longo, Kaeberlein, Fields & Kennedy but the impact of these papers was crushed by 3 irreproducible results that were amplified by global attention, countless news articles nytimes.com/2007/07/08/bus… & commercial hype.

Just as DS never acknowledges the fact that SIR2 is not conserved as a longevity gene in yeast, the proponents of what has turned into a sirtuin cult continue to cite 3 deeply misleading papers. 1st, they claim that extra copies of SIR2 extend lifespan in worms.

2nd, they claim that extra copies of SIR2 extend lifespan in worms. 3rd, they claim that resveratrol is an activator of human SIRT1 that DS found in yeast as a lifespan extender. the collective impact of these 3 results has cost humanity 10s of billions of $ of effort.

We're in the 3rd decade of the cult phase of sirtuin research. It not only drives consumer interest in molecules like resveratrol & pterostilbene, it distorts scientific priorities. A generation of scientists grew up being told that sirtuins were conserved as longevity genes

& due to the impact of DS still publishing in places like @nature & @NatureRevEndo, think that sirtuins are the key mediators of NAD (they're not). More ppl need to know that extra copies of SIR2 do not extend lifespan in flies or worms ncbi.nlm.nih.gov/pmc/articles/P…

that resveratrol is neither a direct activator of sirtuins jbc.org/article/S0021-…

nor a molecule that acts through SIRT1 in cells pubmed.ncbi.nlm.nih.gov/20061378/

and that when DS tried to rescue resveratrol as a direct activator of human SIRT1, he developed a mechanism inconsistent with his reported discovery of resveratrol in a yeast assay. Yeast SIR2 does not have those amino acids. The whole thing is scientifically bankrupt.

How did DS go from an evidence-based yeast researcher to a person completely untethered to science who talks about having yoghurt or olive oil with resveratrol & also not eating til the afternoon, who seems to think that cells "source" ribose & get phosphate from bone,

who conducts non blinded experiments in which he's already announced the results in books & podcasts, who tells people he's reversed his age, who still says he's activating the longevity genes that he found in yeast?

This is a system failure. He wanted to proposes exciting implications from his work on yeast & had a great story about resveratrol explaining the French paradox. The game should have been up when it was revealed that SIR2 shortens lifespan in yeast but few ppl noticed bc

of the nonreproducible fly & worm papers. When @gsk folded the Sirtris program, it could also have been the end of the line but the storytelling has just gotten more creative. Kudos to @NIH for asking me to speak immediately after DS in the recent NAD mtg.

~100 ppl saw DS try to say that MIB-626 is not a naturally occurring NAD metabolite (it's a crystal form of NMN). Science depends on ppl who tell the truth, who test & disprove hypotheses, & who build on solid knowledge to get closer to understanding nature.

Know that I am not the only person calling out this behavior. Academic & industry ppl globally are aware of the problem. It speaks volumes that David has moved his scicomms to podcasts & IG & has no response to SIR2 as not a longevity gene, etc etc etc. He's not evidence-based.🔚

(correction: 2nd, they claim extra copies of SIR2 extend lifespan in flies)