Sirt1 Conditional Knockout mouse models

Sirt1, ortholog of human SIRT1, encodes an NAD+ dependent class III deacetylase whose catalytic core couples removal of acetyl groups to cleavage of NAD+ into nicotinamide and 2-O-acetyl-ADP-ribose, making activity a direct function of cellular NAD+ and a target of nicotinamide product inhibition. Substrates include p53 Lys382, FOXO factors, PGC-1 alpha, NF-kappaB p65 Lys310 and histone H4 Lys16, placing the enzyme at the intersection of stress response, mitochondrial biogenesis and inflammatory transcription, and it is allosterically activated by resveratrol-class compounds through an amino-terminal domain in a substrate-dependent manner. Germline deletion causes substantial perinatal lethality with developmental eye and cardiac defects on most backgrounds, favoring conditional nulls, while catalytically dead histidine to tyrosine knockins distinguish deacetylase activity from scaffolding. Because the allosteric activator site is itself the pharmacological question, activator-insensitive point knockins are often more informative than deletion when validating small molecule mechanism.

A floxed Sirt1 allele paired with Cre gives spatial control that whole body knockouts cannot offer. People use it to separate developmental roles from adult homeostasis, to model somatic mutations, and to match disease that begins in one organ.