Thread by @CharlesMBrenner

lots of ppl have requested a summary of the 1st hr of nia.nih.gov/news/virtual-w… in which @davidasinclair & I spoke back to back. ~200 ppl attended. it was recorded by @nih for their benefit & many of us took notes /1

David began by claiming that he & others have discovered 7 genes called sirtuins that are longevity genes & that are primary mediators of the effects of boosting NAD. He showed a diagram of a man's body in which SIRTs were shown in essentially every tissue as key NAD mediators /2

He showed work from Shin Imai that got him interested in NMN. Said that while others use NR to boost NAD, he uses NMN & that it rejuvenates mice by activating SIRT1. He also referred to lab member(s) working on resveratrol, which he claimed is a SIRT1 activator /3

Halfway through the talk, he said he was putting his Metro Biotech hat on. Said that they are a clinical stage company that employs proprietary compounds that are not naturally occurring including MIB-626 to boost NAD /4

Surprising bc metrobiotech.com/aboutus the company tells everyone that they are "manufacturing a naturally occurring proprietary human clinical grade NAD+ enhancer". David showed data on slide 19 marked control vs NMN--attendees were aware that he's told tens of millions of ppl /5

that he personally takes clinical grade NMN & that he's rejuvenated himself with his daily regimen. So it was incredibly confusing when he said the company was not using naturally occurring compounds in their experiments /6

When David finished, I asked him to go back to slide 19 & clarify if he'd been showing us data on NMN. Dozens of ppl independently commented to me on David's body language. First David said that I was causing a food fight. I said no, I am asking whether you are using NMN /7

He repeated that the company does not use naturally occurring compounds. I replied, if this is a crystal form of NMN, it's NMN in solution as it acts in an animal or a person. He started to say again that it's not naturally occurring & then admitted it is a crystal polymorph. /8

Another attendee asked if NMN gets into cells intact, is it a problem that NMN activates SARM1-dependent neurodegeneration--he does not think so. He was also asked if he is not involved in NAD-boosting supplements, why is he named on the Elysium website. He wasn't sure /9

So after the first 30 min of the conference, we've been set up to believe that sirtuins are longevity genes, SIRTs are the key mediators of NAD, resveratrol is a SIRT1 activator &, for reasons unclear, David doesn't want to admit that Metro's lead compound is crystalline NMN /10

I took the conference all the way back to what I call the 2 rules of biology: no violating chemistry or physics & things are the way they are bc of mutation/selection & encoding in DNA. we can truly understand all things in biology w these 2 rules /11

Living things do not violate the 2nd law of thermodynamics (tendency toward increased entropy) bc we're not closed systems. We take in energy (ie food, which was earlier solar energy) to grow & self-repair during our lifetimes though, in the end, entropy always wins /12

All living things have characteristic lifespans that are encoded in DNA. Animals, which have been around for ~600 M yrs, have a common body plan, etc due to conserved genes--metabolic pathways are much older while mammalian, primate & human-specific traits are much younger /13

I then cited the work of Michael Rose, whose work has been profoundly influential scholar.google.com/citations?user… By the time his @OUPAcademic book Evolutionary Biology of Aging was published in '91, it was clear that animals evolved to 1) acquire food, 2) avoid predation, /14

3) achieve early fertility, 4) have high fecundity &/or good caretaking of offspring until they can do 1-3, 5) have multiple rounds of reproduction. In general, animals expire at the same time they can no longer reproduce. There's no specific longevity program other than /15

fitness required to maintain reproductive success. Human females are an exception. Bc our offspring are so incapable of successful reproduction wo maternal support, human females evolved to outlive their reproductive capacity by 1 generation. Men, on the other hand, have a /16

(declining) sperm count & sex appeal until we expire just like all other animals. This view of evolution means that animal brains, musculature, circulatory & other systems evolved to support however long our reproductive programs function. Rose tested this by keeping M & F /17

flies separate til near their expected lifespan before mating them--only by selecting for late life fertility for 100s of generations could he get long lived flies. The flies were also not long lived bc of monogenic longevity genes but rather contained 100s of variants /18

that support fitness of every part of the fly required to keep it virile longer. Thus, by '91, it was already an unreasonable to expect there to be monogenic longevity genes conserved among animals (even less likely that monogenic longevity genes were conserved with yeast) /19

However, the '90s were an amazing decade in mol bio w lots of received wisdom proved wrong. Around Y2K, Guarente, Sinclair & others claimed to have discovered yeast SIR2 as a longevity gene that was conserved throughout animal evolution as a longevity gene. Did they? /20

I explained that there are 2 types of lifespan assays in baker's yeast. In chronological aging--the amount of time a cell can remain viable after growing to stationary phase--yeast sir2 deletion mutants live longer cell.com/fulltext/S0092… not shorter /21

In the type of aging in which extra copies of SIR2 confer an advantage, yeast mother cells are arrayed on a petri dish & daughter cells are removed after every cell division. The SIR2 advantage appears after ~20 divisions--these old mothers can go ~35 times rather than ~20 /22

While literally any cell in the culture can regenerate the whole culture, Guarente & coworkers were claiming that the SIR2 gene was conserved thru evolution as a longevity gene when the phenotype appears in incredibly rare cells (less than 1 in 2 to the 21st power) /23

This is even more unreasonable when one considers the longer chronological lifespan phenotype of sir2 loss & the fact that the molecular target of the cell division phenotype David described (ribosomal DNA circles) are not found in other organisms /24

Nonetheless, "SIR2 was conserved as a longevity gene story" was highly influential by establishing model bias (let's see whether sirtuins promote longevity) & confirmation bias (+ results are exciting & will be published whereas - may never see the light of day) /25

In '01 Guarente lab claimed that worm SIRT1 extends lifespan & in '04 another group reported that fly SIRT1 extends lifespan. 10s of 1000s of papers followed that carried both biases. Companies were formed--one explicitly based on resveratrol as a SIRT1 activator. Publicists /26

& media exposure played a huge role in the sirtuin wave. David has been all over Time, Newsweek, NY Times, Charlie Rose, Oprah, etc telling the world about the amazing discovery of yeast SIR2 having been conserved as a longevity gene & his discovery that the red wine compound /27

is an activator that will extend human lifespan. The problem is that no part of this is true. Resveratrol is not a SIRT1 activator. In fact, David's latest theory of how it binds to human SIRT1 makes it impossible that it could have been discovered as extending yeast lifespan /28

Investigators from 9 institutions showed that SIRT1 does not extend lifespan in worms or flies ncbi.nlm.nih.gov/pmc/articles/P… --just as the resveratrol result was an artifact that David will not admit to, SIR2 is only a longevity gene in one model of yeast aging & is not a reliable /29

pointer into animal longevity. Everyone knows that resveratrol & Sirtris compounds failed to have SIRT1-dependent activity & failed clinically @GSK despite billions of $ of investment. The global effort on sirtuins would be measured in 10s of billions $ /30

But most importantly, sirtuins are arguably the least regulated enzymes that depend on any of the 4 NAD coenzymes that are essential for moving high energy electrons that make life possible! /31

NAD+ is required for all fuel oxidation, NADH for most ATP generation, NADP+ & NADPH for anabolic reactions & detoxification of reactive oxygen species. Mis-spent effort on sirtuins has created a huge opportunity cost on the NAD field by creating the unreasonable expectations /32

We & others have shown that the NAD system is disturbed by many different conditions of metabolic stress and disease processes (alcohol use, overweight, noise-induced hearing loss, DNA damage, reactive oxygen species, infection, inflammation, heart failure, neurodegeneration, /33

postpartum, etc) such that getting NAD levels back to normal restores metabolic processes, David posits magical models that SIRT genes work worse as you age bc your NAD declines. It's damaging to science & to public trust in science bc it is evidence-free. He's caused /34

investors to lose billions before & now has his sights set on new investors as well as consumers who will believe that he has a kit that allows you to measure your age (spoiler alert: no functional test validates the kit) /35

@nih has reason to be excited about NAD. Preclinical studies show many conditions that have been addressed by restoring NAD. Participants were particularly excited about reversing fatty liver, accelerating wound healing, preventing or treating coronavirus infection, kidney & /36

neuroprotection, as well as developing treatments for heart failure. When we see key metabolites like NAD+ or NADPH under attack accompanied by up-regulation of the NR kinase genes, we can justify NR trials. It's just not helpful for fantastical ideas to persist long after /37

they've been tested & found to be incorrect. Sirtuin mythology is thankfully in decline while interest in the redox metabolism catalyzed by 4 NAD coenzymes is ascendant. Let's try to keep it real from now on? Thanks for reading /end