Discussing Sir2, Sirt1 and Longevity

Some interesting comments on the Sir2 gene - and the equivalent in mammals, Sirt1 - in relation to recent longevity research in yeast can be found in an ongoing discussion thread at the Immortality Institute. A large extension in life span in yeast was attained by deactivating the Sir2 gene - which is interesting, because previous studies suggested that overexpression of the mammalian equivalent (Sirt1) in mice was connected with an extended life span as a result of calorie restriction. It seems that studies on mice lacking Sirt1 have already been run:

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.

Biochemistry is a complicated business, but there is clearly something of interest buried in the mechanisms connected to these genes. The bottom line would be whether or not scientists can establish a safe genetic change or gene therapy for adult humans that manipulates our metabolism to lead to significant extension of healthy life span. I should note that there is some debate and uncertainty over which of the six or more Sirt varieties in humans is actually the equivalent of Sir2, and whether what is true in mice is also true in humans when it comes to these mechanisms by which calorie restriction extends healthy life span. To throw another interesting result into the mix, one study suggests that Sirt1 in mice can act to reduce life span:

We showed that, unlike in yeast, mouse SIRT1 can function to suppress cellular longevity rather than to promote it. That has been a big surprise to the field since it does not fit with preconceived notions of the role of SIRT1.

That researchers can greatly extend life span in lower animals doesn't necessarily mean the same or similar mechanisms will do the same in humans - but that's what we're waiting to find out. Meanwhile, beyond the presently active and funded area of the genetics of longevity, calorie restriction and calorie restriction mimetics, there is a whole range of promising potential scientific anti-aging research - with far greater payoffs than metabolic tinkering could achieve - that is yet to take off or win the needed widespread support. In short, we could be moving forward to longer, healthier lives much more rapidly and directly than at present.

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