Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Summary

Foundational biochemistry paper establishing that yeast Sir2 — the founding member of the sirtuin family — is an NAD+-dependent histone deacetylase rather than a conventional deacetylase. Using purified recombinant Sir2 and reconstituted acetylated histone substrates, Imai and colleagues showed that deacetylase activity was strictly dependent on NAD+ as a cosubstrate, with nicotinamide and O-acetyl-ADP-ribose as reaction products. This mechanistic finding linked cellular NAD+ concentration directly to chromatin silencing and, by extension, to gene regulation, genomic stability, and lifespan. The paper reframed NAD+ from a simple redox cofactor into a signaling molecule coupling metabolic state to transcriptional output. It launched two decades of sirtuin biology across seven mammalian homologs (SIRT1-7) and provided the theoretical basis for why NAD+ decline with age would impair deacetylase-dependent stress responses, mitochondrial function, and DNA damage repair. Nearly every subsequent NAD+-aging hypothesis cites this work as the mechanistic anchor.

Access the full paper

Related research