Sir2 (whose homolog in mammals is known as SIRT1, SIR2L1 or Sir2α) is the namesake of a family of closely related enzymes, the sirtuins (Sir-two-ns). Members of this family have been found in nearly all organisms studied. 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.
Nomenclature in various organisms
Sir2 is short for Silent mating type Information Regulation-2 and sirtuin stands for Sir2-homolog.
Method of action and observed effects
Sirtuins act by removing acetyl groups from proteins in the presence of NAD+; they are thus classified as "NAD+-dependent deacetylases" and have EC number 3.5.1. They add the acetyl group from the protein to the ADP-ribose part of NAD+ to form O-acetyl-ADP-ribose.
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 deacetylating (removing an acetyl group from) histone molecules, which results in tighter packaging and lower level of transcription of the cell's DNA. Sir2 is thus classified as a histone deacetylase.
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. Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster support these findings. As of 2006, experiments in mice are underway.
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  Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
Resveratrol is a substance which experiments have shown to have 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. However, these claims are controversial: it has been reported that the observed effect of resvertatrol on Sir2 activity is likely an artifact of the experimental setup and does not reflect biological reality.
In the fruit fly Drosophilia melanogaster the Sir2 gene does not seem to be essential; loss of a sirtuin gene only has very subtle effects. However mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.
Seven sirtuins are known in mammals.
- SIRT1 (also known as Sir2α) is the mammal homolog of Sir2. Mice that overexpress SIRT1 show eight properties of calorie restriction, including low cholesterol, low blood glucose, and low insulin levels. They also show increased numbers of mitochondria in their neurons.
- SIRT2 is mainly expressed in the brain.
- SIRT3, SIRT4, and SIRT5 are active in mitochondria, the energy producing organelles that are a part of every cell.
- SIRT6 is active in the nucleus of the cell.
- SIRT7 is active in the nucleolus, a compartment of the nucleus reserved for the assembly of ribosomes, the makers of proteins.
- Histone deacetylases, the class of enzymes yeast Sir2 belongs to.
- Longevity genes
- Life extension
- Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8. PMID: 10873683
- Sinclair DA, Guarente L. Unlocking the Secrets of Longevity Genes. Scientific American, March 2006, pp 48-57, full text
- Sirt1, from iHOP database
- Frye R (2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochem Biophys Res Commun. 273 (2): 793–8. PMID 10873683.
- The Sir2 protein family from EMBL's InterPro database
- Drosophilia 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.
- Human Sirt1 from NCBI's Entrez Gene database
- McBurney et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 2003 Jan;23(1):38-54. PMID 12482959
- Human Sirt1 from NCBI's Entrez Gene database
- Human Sirt1 in the GenAge database
- Sirt1 in the iHOP database