Sir2

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.^[1] 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]

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Nomenclature in various organisms

Sir2 is short for Silent mating type Information Regulation-2 and sirtuin stands for Sir2-homolog^[3].

The name Sir2 is used for the enzyme in the yeast Saccharomyces cerevisiae (where it was first discovered), in the fruit fly Drosophila melanogaster and in the roundworm Caenorhabditis elegans.^[4]

The various sirtuins in mammals are named SIRT1, SIRT2, SIRT3 etc. and SIRT1 is the mammalian homolog (sometimes claimed to be ortholog) of Sir2.^[5][6]

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.^[7] 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.^[8] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster^[9] support these findings. 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 ^[10] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.^[11]

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.^[2] 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.^[12][13]

In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the p53 protein.^[14]

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.^[8] However mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.^[15]

Mammal sirtuins

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.

See also

• Histone deacetylases, the class of enzymes yeast Sir2 belongs to.
• Longevity genes
• Life extension
• Sirtuin

References