GenAge entry for SIRT1 (Homo sapiens)

Gene name (HAGRID: 0150)

HGNC symbol: SIRT1
Aliases: SIR2L1
Common name: sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)

Potential relevance to the human ageing process

Main reason for selection

Entry selected based on evidence directly linking the gene product to ageing in a non-mammalian animal model

Description

SIRT1 is a NAD-dependent deacetylase, which has the ability to regulate a number of processes by deacetylating key proteins, such as TP53 [0734]. In yeast, the SIRT1 homologue sir2 has been linked to cellular senescence [0200]. Increasing the levels of SIRT1 homologues in fruit flies [1284] and roundworms [0199] extends lifespan.

SIRT1-null mice are born smaller than controls with evidence of developmental retardation. Depending on their genetic background, SIRT1-null mice either die shortly after birth or reach adulthood, the latter being smaller than controls and sterile [0201]. Heterozygous mice had a normal average lifespan [1922]. SIRT1 is overexpressed in calorie restricted rats, a response attenuated by insulin (INS) and IGF1 [1328]. Increased dosage of SIRT1 in pancreatic beta cells enhanced INS secretion [1481]. Mice with moderate overexpression of SIRT1 exhibit fat mass gain similar to controls exposed to a high-fat diet [1897]. Cardiac-specific low to moderate overexpression of SIRT1 attenuated age-dependent increases in cardiac hypertrophy, apoptosis, and expression of senescent biomarkers while a high level of overexpression had detrimental effects and induced cardiomyopathy [1930]. Although SIRT1 could impact on age-related diseases, such as type 2 diabetes, further studies are needed to establish its role in human ageing.

Cytogenetic information

Cytogenetic band: 10q21.3
Location: 69,314,432 bp to 69,348,147 bp
Orientation: Plus strand

Display region using the UCSC Genome Browser

Protein information

Gene Ontology

Process:

GO:0006350; transcription
GO:0006355; regulation of transcription, DNA-dependent
GO:0006915; apoptosis
GO:0007275; multicellular organismal development
GO:0007519; skeletal muscle development
GO:0030154; cell differentiation
GO:0044419; interspecies interaction between organisms

Function:

GO:0003677; DNA binding
GO:0008270; zinc ion binding
GO:0046872; metal ion binding
GO:0051287; NAD binding

Cellular component:

GO:0005634; nucleus
GO:0005677; chromatin silencing complex

Protein interactions and network

Protein-protein interacting partners in GenAge: EP300
IDG: Display interactions using the IGD
STRING interaction network

Retrieve sequences for SIRT1

ORF: ORF
CDS: CDS

Homologues in model organisms

Caenorhabditis elegans: sir-2.1
Drosophila melanogaster: Sir2
Mus musculus: Sirt1

In other databases

GenDR

This gene is present in the GenDR gene manipulations database for Caenorhabditis elegans.
This gene is present in the GenDR gene manipulations database for Drosophila melanogaster.

GenAge

This gene has the homolog sir-2.1 in GenAge for Caenorhabditis elegans
This gene has the homolog Sir2 in GenAge for Drosophila melanogaster

AnAge

This species has an entry in AnAge

Selected references

[1967] Yao et al. (2012) SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice., PubMed
[1968] Libert et al. (2011) SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive., PubMed
[2024] Palacios et al. (2010) SIRT1 contributes to telomere maintenance and augments global homologous recombination., PubMed
[2074] Min et al. (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy., PubMed
[2025] Satoh et al. (2010) SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus., PubMed
[2027] Donmez et al. (2010) SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10., PubMed
[2028] Calvanese et al. (2010) Sirtuin 1 regulation of developmental genes during differentiation of stem cells., PubMed
[2023] Gao et al. (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134., PubMed
[1969] Morselli et al. (2010) The life span-prolonging effect of sirtuin-1 is mediated by autophagy., PubMed
[1991] Cakir et al. (2009) Hypothalamic Sirt1 regulates food intake in a rodent model system., PubMed
[2020] Cohen et al. (2009) Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction., PubMed
[2022] Boily et al. (2009) SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol., PubMed
[1999] Ramsey et al. (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis., PubMed
[1989] Nie et al. (2009) STAT3 inhibition of gluconeogenesis is downregulated by SirT1., PubMed
[2001] Nakahata et al. (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1., PubMed
[1970] Westerheide et al. (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1., PubMed
[2117] Oberdoerffer et al. (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging., PubMed
[1990] Wang et al. (2008) Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice., PubMed
[2026] Chen et al. (2008) The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration., PubMed
[2120] Nakahata et al. (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control., PubMed
[1897] Pfluger et al. (2008) Sirt1 protects against high-fat diet-induced metabolic damage, PubMed
[1922] Li et al. (2008) SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons, PubMed
[2021] Chen et al. (2008) Tissue-specific regulation of SIRT1 by calorie restriction., PubMed
[1896] Li et al. (2008) Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation, PubMed
[2121] Narala et al. (2008) SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity., PubMed
[1850] Gates et al. (2007) Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease, PubMed
[1901] Sun et al. (2007) SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B, PubMed
[1898] Bordone et al. (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction, PubMed
[1921] Kim et al. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis, PubMed
[1930] Alcendor et al. (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart, PubMed
[1846] Gerhart-Hines et al. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha, PubMed
[1935] Hida et al. (2007) Strong expression of a longevity-related protein, SIRT1, in Bowen's disease, PubMed
[1894] Sommer et al. (2006) DeltaNp63alpha overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse, PubMed
[1810] Sasaki et al. (2006) Progressive loss of SIRT1 with cell cycle withdrawal, PubMed
[1936] Fu et al. (2006) Hormonal control of androgen receptor function through SIRT1, PubMed
[1804] Wang et al. (2006) Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage, PubMed
[1801] Longo and Kennedy (2006) Sirtuins in aging and age-related disease, PubMed
[1818] Sauve et al. (2006) The biochemistry of sirtuins, PubMed
[1776] Qin et al. (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer's disease amyloid neuropathology by calorie restriction, PubMed
[1770] Kolthur-Seetharam et al. (2006) Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage, PubMed
[1808] Pruitt et al. (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation, PubMed
[1601] Jeon et al. (2006) MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance, PubMed
[1586] Kamel et al. (2006) SirT1 fails to affect p53-mediated biological functions, PubMed
[1616] Bordone et al. (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells, PubMed
[1566] Flachsbart et al. (2006) Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity, PubMed
[1558] Anekonda and Reddy (2006) Neuronal protection by sirtuins in Alzheimer's disease, PubMed
[1653] Ota et al. (2006) Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells, PubMed
[1570] Kaeberlein et al. (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients, PubMed
[1583] Greer and Brunet (2005) FOXO transcription factors at the interface between longevity and tumor suppression, PubMed
[1806] Ford et al. (2005) Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival, PubMed
[1564] Fabrizio et al. (2005) Sir2 blocks extreme life-span extension, PubMed
[1582] Chen et al. (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses, PubMed
[1769] Pillai et al. (2005) Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity, PubMed
[1574] Chen et al. (2005) SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling, PubMed
[1481] Moynihan et al. (2005) Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice, PubMed
[1575] Michishita et al. (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins, PubMed
[1480] Chua et al. (2005) Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress, PubMed
[1547] Guarente (2005) Calorie restriction and SIR2 genes--towards a mechanism, PubMed
[1300] Rodgers et al. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1, PubMed
[0173] Nemoto et al. (2004) Nutrient availability regulates SIRT1 through a forkhead-dependent pathway, PubMed
[1284] Rogina and Helfand (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction, PubMed
[1578] Araki et al. (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration, PubMed
[1285] Wood et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans, PubMed
[1095] Daitoku et al. (2004) Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity, PubMed
[1328] Cohen et al. (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase, PubMed
[1068] Blander and Guarente (2004) The sir2 family of protein deacetylases, PubMed
[1138] Picard et al. (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma, PubMed
[1805] Yeung et al. (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase, PubMed
[1071] Motta et al. (2004) Mammalian SIRT1 represses forkhead transcription factors, PubMed
[0990] Brunet et al. (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase, PubMed
[0980] Cheng et al. (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice, PubMed
[1710] Fulco et al. (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state, PubMed
[0201] McBurney et al. (2003) The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis, PubMed
[0177] Newman et al. (2002) A Drosophila homologue of Sir2 modifies position-effect variegation but does not affect life span, PubMed
[0202] Rogina et al. (2002) Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction, PubMed
[1425] Hoopes et al. (2002) Mutations in DNA replication genes reduce yeast life span, PubMed
[0734] Langley et al. (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence, PubMed
[0735] Vaziri et al. (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase, PubMed
[1070] Luo et al. (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress, PubMed
[0199] Tissenbaum and Guarente (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans, PubMed
[0200] Kaeberlein et al. (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms, PubMed
[1493] Tsukamoto et al. (1997) Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae, PubMed