Glossary
Sirtuin
Sirtuins (SIRT1-7) are NAD+-dependent deacylases, each with its own location in the cell. What they do, and why the NAD+ supply controls how active they are.
The sirtuins are seven mammalian enzymes, SIRT1 to SIRT7, that strip acetyl and other acyl groups from lysine residues. What sets them apart is their chemistry: in contrast to class I/II histone deacetylases, they need NAD+ as a co-substrate and use up one NAD+ for every deacylation, liberating nicotinamide and 2’-O-acyl-ADP-ribose. Because of this one-to-one stoichiometry, sirtuin activity responds directly to how much NAD+ the cell has.
Locations and targets
Every member has its own location and set of substrates: SIRT1 and SIRT6/7 are mostly nuclear and modify histones and transcription factors such as PGC-1alpha, p53 and FOXO; SIRT3, SIRT4 and SIRT5 are mitochondrial, with SIRT3 deacetylating enzymes of fatty-acid oxidation and the electron transport chain; SIRT2 is found mainly in the cytoplasm and targets tubulin. This is the mechanistic connection between NAD+ precursors like NMN and the transcriptional and mitochondrial endpoints described in ageing models.
Interpret the literature with care. Early lifespan claims for Sir2 in yeast and invertebrates were considerably revised once replication was attempted, and reports of resveratrol directly activating SIRT1 were muddied by artefacts from the assay fluorophore. Current research relies more on genetic models and on NAD+ availability than on direct activation by small molecules.
Related terms and material
AMPK · senolytic · preclinical. Reference material: NAD+, spermidine, longevity peptides. Further reading: peptides for anti-aging research.