Thread by @mkaeberlein

Sort of. For anyone who cares, here is a chronology of the Dawn of Sirtuins, at least as I remember it... /1

https://twitter.com/CharlesMBrenner/status/1412502316414996480

Nic Austriaco and @BKennedy_aging were studying aging in yeast and identified a lifespan extending mutation in a protein called Sir4 (not a sirtuin) that physically interacts with Sir2 at telomeres. /2

pubmed.ncbi.nlm.nih.gov/7859289/

They didn't know exactly how it worked but knew it affected distribution of Sir4 from telomeres to the nucleolus and that this mutation delayed degradation of the nucleolus with age

Soon after that @davidasinclair discovered that rDNA circles are caused by instability in the rDNA (which resides in the nucleolus) and accumulate in mother cells. They proposed that these extrachromosomal rDNA circles (ERCs) cause yeast aging. /4
pubmed.ncbi.nlm.nih.gov/9428525/

I joined the Guarente lab as a grad student and, along with Mitch McVey, showed that overexpressing Sir2, which also acts in the nucleolus, was sufficient to extend lifespan in yeast. At this point nobody knew what the biochemical function of Sir2 was. /5
pubmed.ncbi.nlm.nih.gov/10521401/

Soon after that, a post-doc in the lab, Shin Imai discovered that Sir2 was an NAD-dependent deacetylase (that's the link to NAD)

pubmed.ncbi.nlm.nih.gov/10693811/

Su-Ju Lin, another post-doc in the lab, connected Sir2 and NAD+ to caloric restriction around the same time /6 (I think... not very good at the numbers)

pubmed.ncbi.nlm.nih.gov/11000115/

Heidi Tissenbaum, another post-doc, found that overexpressing the Sir2 homolog in in worms, Sir-2.1, could extend lifespan in worms. This was really the moment I think people outside the Guarente lab started believing in sirtuins as aging regulators. /7
pubmed.ncbi.nlm.nih.gov/11242085/

I've co-authored papers questioning both the link to CR in yeast and lifespan effects in worms /8
pubmed.ncbi.nlm.nih.gov/15328540/
pubmed.ncbi.nlm.nih.gov/21938067/

To be clear, I don't think anyone did anything wrong. This is how science is supposed to work. Models are by definition imperfect and we strive to do experiments to break the models and make them better /9