Sirtuin 1, also known asNAD-dependent deacetylase sirtuin-1, is aprotein that in humans is encoded by theSIRT1gene.[5][6][7]
SIRT1 stands forsirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that itssirtuin homolog (biological equivalent across species) in yeast(Saccharomyces cerevisiae) is Sir2. SIRT1 is anenzyme located primarily in thecell nucleus that deacetylatestranscription factors that contribute to cellular regulation (reaction to stressors, longevity).[8][9]
Sirtuin 1 is a member of the sirtuin family of proteins,homologs of the Sir2 gene inS. 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 regulateepigenetic 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 highinsulin resistance.[10] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of thePGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[11][12]
In vitro, SIRT1 has been shown to deacetylate and thereby deactivate thep53 protein,[13] and may have a role in activatingT helper 17 cells.[14]
Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study onprogeria.[15]
Resveratrol has been claimed to be an activator of sirtuin 1,[16] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.[17][18] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[10] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[19][20] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[15] In addition to resveratrol, a range of other plant-derivedpolyphenols have also been shown to interact with SIRT1.[21]
SRT-1720 and related compounds such asSRT2104 have been claimed to be SIRT1 activators,[16] but this has subsequently been questioned.[22][23]
Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation ofAMP-activated protein kinase (AMPK),[26] which increasesNAD+ levels (which is thecofactor required for SIRT1 activity).[27][28] Elevating NAD+ is a more direct and reliable way to activate SIRT1.[28]
Sir2 (whosehomolog inmammals is known asSIRT1) was the first of thesirtuin genes to be found. It was found inbudding yeast, and, since then, members of thishighly conserved family have been found in nearly all organisms studied.[31] 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 ofcalorie restriction.[32][33]
The three letter yeast gene symbolSir stands forSilentInformationRegulator while the number2 is representative of the fact that it was the second SIR gene discovered and characterized.[34][35]
In the roundworm,Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[36][37]
Sirtuins act primarily by removingacetyl groups fromlysine residues within proteins in the presence ofNAD+; thus, they are classified as "NAD+-dependent deacetylases" and haveEC number 3.5.1.[38] They add the acetyl group from the protein to theADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging ofchromatin and a reduction intranscription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, thehidden MAT loci (HM loci), and theribosomal DNA (rDNA) locus (RDN1) from whichribosomal RNA is transcribed.
Limitedoverexpression of the Sir2gene results in a lifespan extension of about 30%,[39] 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.[39] 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.[40] 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, reduceshomologous 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.[40]
Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reducesnicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.[41] Experiments in thenematodeCaenorhabditis elegans and in the fruit flyDrosophila melanogaster[42] support these findings. As of 2006[update], experiments inmice are underway.[32]
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 actuallyincreases lifespan[43] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[44]
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
In the fruit flyDrosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[41] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[45]
Human aging is characterized by a chronic, low-grade inflammation level,[46] and thepro-inflammatorytranscription factorNF-κB is the main transcriptional regulator of genes related to inflammation.[47] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[48][49] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of themicroRNAmiR-34a (which inhibitsnicotinamide adenine dinucleotide NAD+ synthesis) by binding to itspromoter region,[50] resulting in lower levels of SIRT1.
Both the SIRT1 enzyme and the polyADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation.[51] PARP1 is aDNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20–30% thereby reducing SIRT1 activity.[51]
SIRT1 protein actively promoteshomologous recombination (HR) in human cells, and likely promotes recombinationalrepair of DNA breaks.[52] SIRT1-mediated HR requires theWRN protein.[52] WRN protein functions in double-strand break repair by HR.[53] WRN protein is aRecQ helicase, and in its mutated form gives rise toWerner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.[52]
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