our lab's foundational discovery is that the 4 NAD coenzymes, Crown Jewels of metabolism, are not locked in a vault inside a castle & patrolled by guards. instead, they are exposed to the elements of metabolic stress. many conditions of metabolic stress disturb NAD systems. /1
alcohol, overnutrition, deafening sound, DNA damage, ROS, heart failure, neurodegeneration, inflammation & infection ALL disturb NAD systems in one or more tissues. aging reportedly disturbs NAD, though the evidence is weaker than in all other conditions. /2
when NAD comes under attack, repair processes are compromised, ATP generation is impaired & anabolic processes are disturbed. attributing all of NAD metabolism to SIRTs is just dumb & should have been checked by good reviewers >10,000 publications ago. /3
I've reviewed dumb papers in which ppl look for an effect of SIRT1 (almost always indirect & correlative such as p53 acetylation) & don't see it (remember this would not demonstrate that SIRT1 is responsible for an effect, just correlated with it) & then they look for SIRT2! /4
as I told audience @Georgetown on thurs, SIRTs are interesting NAD-dependent enzymes but are NOT required for any major tissue function in a mammal. try living without pyruvate DH or fatty acid synthase, just to name 2 of 100s of important NAD+ or NADPH-dependent enzymes. /5
repleting NAD system when NAD is under attack is clearly pleiotropic, meaning that dozens of functions work better. editors like simple mechanisms but good stories with weak data keep getting published & contaminating the literature with bogus claims. /6
among the NAD-consuming enzymes, SARM1, CD38 and every PARP I know are far more regulated than any SIRT. SARM1 is OFF until stimulated by NMN. CD38 can't make NAADP until IL8 system. PARPs are either turned on post-translationally or massively induced by transcription /7
note to @FASEBorg conference organizers & reviewers: stop with the SIRT hype. there is so much more to the NAD field in redox metabolism, cell death, Ca@+ signaling and MAR/PARylation than in the attribution of NAD regulation to SIRTs /end
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