Sir2 has been characterised as a histone deacetylase. It stands for Silent Information Regulator because it actually induces the "silencing" or reduction of expression in specific regions of DNA. Such enzymes catalyze the removal of the acetyl component of histones. Histones can be described as scaffolds around which DNA is bound. The "tightness" of DNA binding to histones is a determinant of whether the genetic information encoded by DNA in that region can be transcribed or not. When histones are deacetylated (by a histone deacetylase like Sir2) it is generally associated with a reduction of gene expression (silencing) in the DNA that is bound to them. This gene is highly conserved and the mammalian version of Sir2 is called Sirt1.
hopefully it won't take too long to make some knockout mice.
Was already done in 2003 (1). What they found in the mice that were able to survive that despite growth defects and sterility that they shared some of the effects associated with long lived IGF1-deficient mice. It appears that Sirt1 has a developmental function and should not be altered during embryonic development. So the interesting question is why would Sir2 overexpression confer a modest lifespan increase but Sir2 deletion confer substantial lifespan extension? The clues could lie in which genes are silenced by Sir2/Sirt1. One gene that is silenced by Sirt1 is Foxo3a (2), a gene responsible for protection from oxidative stress (3) and DNA repair (4).
In any case, it would appear that if the life extension effects of Sir2/Sirt1 downmodulation are to be applied to mammalian systems they must be done so only in somatic cells (not germline or stem cells) and then only once development has been completed.
(1) Mol Cell Biol. 2003 Jan;23(1):38-54.
The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis.
McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M.
(2) Cell. 2004 Feb 20;116(4):551-63.
Mammalian SIRT1 represses forkhead transcription factors.
Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L.
(3) Nature. 2002 Sep 19;419(6904):316-21
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM.
(4) Science. 2002 Apr 19;296(5567):530-4.
DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein.
Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW, Greenberg ME.