Sirtuin 1

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.^[5][6][7]

SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).^[8][9]

Function

Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. The protein encoded by this gene is included in class I of the sirtuin family.^[6]

Sirtuin 1 is downregulated in cells that have high insulin resistance.^[10] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.^[11][12]

In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein,^[13] and may have a role in activating T helper 17 cells.^[14]

Selective ligands

Activators

• Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria.^[15]
• Lamin A.^[15] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.^[21]
• SRT-1720 was also claimed to be an activator,^[16] but this now has been questioned.^[22]
• Methylene blue^[23] by increasing NAD+/NADH ratio.
• Metformin activates both PRKA and SIRT1.^[24]

Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK),^[25] which increases NAD+ levels (which is the cofactor required for SIRT1 activity).^[26][27] Elevating NAD+ is a more direct and reliable way to activate SIRT1.^[27]

Interactions

Sirtuin 1 has been shown in vitro to

Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes.[29]

Sir2

Sir2 (whose

The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.[33]^[34]

In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.^[35][36]

Method of action and observed effects

Sirtuins act primarily by removing

Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,^[38] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.^[38] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.^[39] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.^[39]

Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD⁺ and reduces

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 [42] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.^[43]

In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.

In the fruit fly Drosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.^[40] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.^[44]

Inhibition of SIRT1

Human aging is characterized by a chronic, low-grade inflammation level,^[45] and the pro-inflammatory transcription factor NF-κB is the main transcriptional regulator of genes related to inflammation.^[46] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.^[47][48] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of the microRNA miR-34a (which inhibits nicotinamide adenine dinucleotide NAD+ synthesis) by binding to its promoter region.^[49] resulting in lower levels of SIRT1.

Both the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation.^[50] PARP1 is a DNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20-30% thereby reducing SIRT1 activity.^[50]

Homologous recombination

SIRT1 protein actively promotes