Why do I point out that the foundational SIR2 and sirtuin data are deeply flawed? Because more than a decade of papers on yeast, flies & worms shaped expectations of what sirtuins would do in vertebrates (extend lifespan) /1
It is true that sirtuins use NAD+ to modify protein function by removing acyl groups from protein lysines. It is not true that they are essential for the longevity benefit of calorie restriction. It is not true that they are the primary mediators of NAD /2
It is distinctly wrong that they are critical regulators of DNA repair. It is not true that they are essential for mitochondrial biogenesis or mitochondrial function. All of these ideas were suggested, however, by papers in model organisms that turn out to be wrong /3
The early studies created model bias: that SIR2-related genes could best be explained as longevity regulators. And confirmation bias: that these genes would have positive roles in longevity /4
Thus, when ppl looked at sirtuins in flies, worms & mice, they tended to look for longevity advantages & were able to publish papers that showed these positive results. Now we know that many of the foundational papers are not reproducible, were overhyped & are simply wrong. /5
In actual fact, SIR2-related genes don't do the same things in different tissues. We've known for almost 20 years that SIR2 mutants live longer (not shorter) in 1 of the 2 yeast assays for lifespan (chronological lifespan as opposed to replicative lifespan) /6
Rather than look at the data dispassionately, SIR2 proponents told you that sirtuins were conserved as longevity genes. They could have just as easily told you that sirtuins were conserved as antilongevity genes based on yeast but they didn't & they never will /7
Instead, they claim that sirtuins are the 7 most important longevity genes in people (they aren't), that sirtuins mediate the key effects of NAD (no reason to expect they do), & they make up fanciful stories about resveratrol activating SIRT1 (it doesn't) /8
The functions of NAD+, NADH, NADP+ & NADPH are mediated by scores of enzymes that are essential for energy generation & conversion of everything we eat into everything we are & do /9
Though they have been appealing to editors, models that invoke magical sirtuin functions stand on weak premises & are not evidence-based. Time to learn metabolism & especially conditions that disturb the NAD system & realize that SIRT-centric models are the sign of a cult /end
