Sir2
Sir2 is a member of a family of closely related enzymes. Members of this family, also known as sirtuins, have been found in nearly all organisms studied [1]; the mammalian versions are known as Sirt1. Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.[2]
These enzymes act by removing acetyl groups in the presence of NAD+; they are thus classified as "NAD+-dependent deacetylases" and have EC number 3.5.1.[3]
In the yeast Saccharomyces cerevisiae, overexpression of the Sir2 gene results in a lifespan extension of about 30%, if the lifespan is measured as the number of cell divisions the cell can undergo before dying. This is due to Sir2 deacetylasing histone molecules, which results in tighter packaging and thus protection of the cell's DNA. Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both increasing the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of calorie restriction.[4] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[5] have confirmed these findings; it is thus reasonable to conclude that Sir2 is responsible for producing the life-extending effects of calorie restriction. As of 2006, experiments in mice are underway.[2]
However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage , then silencing the Sir2 gene actually increases lifespan [6] Furthermore, calorie restriction can substantially prolong reproductive lifespan even in the absence of Sir2.[7]
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
Resveratrol is a substance which has a number of life-extending and health benefits in various species; it also increases the activity of Sir2 and this is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress.[2] However, these claims are controversial: it has been reported that the observed effect of resvertatrol on Sir2 activity is likely an artefact of the experimental setup and does not reflect biological reality.[8][9]
References
- ^ Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8. PMID: 10873683
- ^ a b c Sinclair DA, Guarente L. Unlocking the secrets of lengevity genes. Scientific American, March 2006, pp 48-57, full text
- ^ The Sir2 protein family from EMBL's InterPro database
- ^ Yeast Sir2 from NCBI's Entrez Gene database
- ^ Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15998-6003. PMID 15520384
- ^ Fabrizio P et al. Sir2 blocks extreme life-span extension. Cell. 2005 Nov 18;123(4):655-67. PMID 16286010
- ^ Kaeberlein M et al. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004 Sep;2(9):E296. PMID 15328540
- ^ Kaeberlein et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29; 280(17):17038-45. PMID 15684413.
- ^ Borra MT et al. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005 Apr 29; 280(17):17187-95. PMID 15749705.
See also
- Histone deacetylases, the class of enzymes yeast Sir2 belongs to.
- Life extension
External links
- Human Sirt1 from NCBI's Entrez Gene database
- Human Sirt1 in the GenAge database