The SIRT1 gene and its putative association with human ageing

HGNC symbol

SIRT1

Aliases

SIR2L1

Common name

sirtuin 1

Main reason for selection

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

Description

SIRT1 is a NAD-dependent deacetylase, which can regulate a number of processes by deacetylating key proteins, such as TP53 [734]. In yeast, the SIRT1 homologue sir2 has been linked to cellular senescence [200]. Increasing the levels of SIRT1 homologues in fruit flies [1284] and roundworms [199] extends lifespan, although these findings have been questioned by other studies [3321].

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 [201]. Additionally, SIRT1-null mice utilize ingested food inefficiently, are hypermetabolic, contain inefficient liver mitochondria, have elevated rates of lipid oxidation and do not display an extended lifespan under caloric restriction [3608]. Heterozygous mice had a normal average lifespan [1922]. 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]. Overall, whole-body moderate overexpression of Sirt1 improves healthy ageing but does not increase mice lifespan [3266]. Brain-specific overexpression in mice results in moderately longer lifespan as females live 16% longer and males 9% longer [3268].

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].

In Cockayne syndrome, an accelerated ageing disease, activation of SIRT1 through a high-fat diet and NAD(+) supplementation results in the rescue the mice from the associated progeroid phenotypes [3605]. In murine induced pluripotent stem cells, SIRT1 is necessary for telomere elongation after reprogramming and is required to maintain genomic stability, telomeric transcription and remodeling of telomeric chromatin. SIRT1-deficient induced pluripotent stem cells accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin [3606]. In humans, increased levels of SIRT1 and SIRT3 have been associated with frailty [3607]. 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 band

10q21.3

Location

67,884,669 bp to 67,918,390 bp

Orientation

Plus strand

Gene Ontology

Process:

GO:0000012; single strand break repair
GO:0000122; negative regulation of transcription from RNA polymerase II promoter
GO:0000183; chromatin silencing at rDNA
GO:0000720; pyrimidine dimer repair by nucleotide-excision repair
GO:0000731; DNA synthesis involved in DNA repair
GO:0001525; angiogenesis
GO:0001542; ovulation from ovarian follicle
GO:0001678; cellular glucose homeostasis
GO:0001934; positive regulation of protein phosphorylation
GO:0001938; positive regulation of endothelial cell proliferation
GO:0002821; positive regulation of adaptive immune response
GO:0006260; DNA replication
GO:0006281; DNA repair
GO:0006325; chromatin organization
GO:0006342; chromatin silencing
GO:0006343; establishment of chromatin silencing
GO:0006344; maintenance of chromatin silencing
GO:0006346; methylation-dependent chromatin silencing
GO:0006364; rRNA processing
GO:0006366; transcription from RNA polymerase II promoter
GO:0006471; protein ADP-ribosylation
GO:0006476; protein deacetylation
GO:0006642; triglyceride mobilization
GO:0006974; cellular response to DNA damage stimulus
GO:0006979; response to oxidative stress
GO:0007283; spermatogenesis
GO:0007346; regulation of mitotic cell cycle
GO:0007517; muscle organ development
GO:0007569; cell aging
GO:0008284; positive regulation of cell proliferation
GO:0009267; cellular response to starvation
GO:0010046; response to mycotoxin
GO:0010460; positive regulation of heart rate
GO:0010629; negative regulation of gene expression
GO:0010667; negative regulation of cardiac muscle cell apoptotic process
GO:0010875; positive regulation of cholesterol efflux
GO:0010883; regulation of lipid storage
GO:0010906; regulation of glucose metabolic process
GO:0010934; macrophage cytokine production
GO:0010976; positive regulation of neuron projection development
GO:0014068; positive regulation of phosphatidylinositol 3-kinase signaling
GO:0014858; positive regulation of skeletal muscle cell proliferation
GO:0016032; viral process
GO:0016239; positive regulation of macroautophagy
GO:0016567; protein ubiquitination
GO:0016575; histone deacetylation
GO:0018394; peptidyl-lysine acetylation
GO:0030225; macrophage differentiation
GO:0030308; negative regulation of cell growth
GO:0030512; negative regulation of transforming growth factor beta receptor signaling pathway
GO:0031393; negative regulation of prostaglandin biosynthetic process
GO:0031648; protein destabilization
GO:0031937; positive regulation of chromatin silencing
GO:0032007; negative regulation of TOR signaling
GO:0032071; regulation of endodeoxyribonuclease activity
GO:0032088; negative regulation of NF-kappaB transcription factor activity
GO:0032720; negative regulation of tumor necrosis factor production
GO:0032868; response to insulin
GO:0032922; circadian regulation of gene expression
GO:0033158; regulation of protein import into nucleus, translocation
GO:0033210; leptin-mediated signaling pathway
GO:0034391; regulation of smooth muscle cell apoptotic process
GO:0034983; peptidyl-lysine deacetylation
GO:0035356; cellular triglyceride homeostasis
GO:0035358; regulation of peroxisome proliferator activated receptor signaling pathway
GO:0035774; positive regulation of insulin secretion involved in cellular response to glucose stimulus
GO:0042127; regulation of cell proliferation
GO:0042326; negative regulation of phosphorylation
GO:0042542; response to hydrogen peroxide
GO:0042595; behavioral response to starvation
GO:0042632; cholesterol homeostasis
GO:0042771; intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:0043065; positive regulation of apoptotic process
GO:0043066; negative regulation of apoptotic process
GO:0043124; negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043161; proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0043280; positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0043392; negative regulation of DNA binding
GO:0043433; negative regulation of sequence-specific DNA binding transcription factor activity
GO:0043518; negative regulation of DNA damage response, signal transduction by p53 class mediator
GO:0043524; negative regulation of neuron apoptotic process
GO:0044321; response to leptin
GO:0045348; positive regulation of MHC class II biosynthetic process
GO:0045471; response to ethanol
GO:0045599; negative regulation of fat cell differentiation
GO:0045722; positive regulation of gluconeogenesis
GO:0045739; positive regulation of DNA repair
GO:0045766; positive regulation of angiogenesis
GO:0045892; negative regulation of transcription, DNA-templated
GO:0045909; positive regulation of vasodilation
GO:0045944; positive regulation of transcription from RNA polymerase II promoter
GO:0046628; positive regulation of insulin receptor signaling pathway
GO:0050872; white fat cell differentiation
GO:0051097; negative regulation of helicase activity
GO:0051152; positive regulation of smooth muscle cell differentiation
GO:0051574; positive regulation of histone H3-K9 methylation
GO:0051898; negative regulation of protein kinase B signaling
GO:0055089; fatty acid homeostasis
GO:0060125; negative regulation of growth hormone secretion
GO:0060766; negative regulation of androgen receptor signaling pathway
GO:0061647; histone H3-K9 modification
GO:0070301; cellular response to hydrogen peroxide
GO:0070857; regulation of bile acid biosynthetic process
GO:0070914; UV-damage excision repair
GO:0070932; histone H3 deacetylation
GO:0071236; cellular response to antibiotic
GO:0071303; cellular response to vitamin B3
GO:0071356; cellular response to tumor necrosis factor
GO:0071441; negative regulation of histone H3-K14 acetylation
GO:0071456; cellular response to hypoxia
GO:0071479; cellular response to ionizing radiation
GO:0071900; regulation of protein serine/threonine kinase activity
GO:0090312; positive regulation of protein deacetylation
GO:0090335; regulation of brown fat cell differentiation
GO:0090400; stress-induced premature senescence
GO:1900034; regulation of cellular response to heat
GO:1900113; negative regulation of histone H3-K9 trimethylation
GO:1900181; negative regulation of protein localization to nucleus
GO:1901984; negative regulation of protein acetylation
GO:1902166; negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:1902176; negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
GO:1902237; positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
GO:1902617; response to fluoride
GO:1903427; negative regulation of reactive oxygen species biosynthetic process
GO:1904179; positive regulation of adipose tissue development
GO:1904373; response to kainic acid
GO:1904638; response to resveratrol
GO:1904644; cellular response to curcumin
GO:1904646; cellular response to beta-amyloid
GO:1904648; cellular response to rotenone
GO:1990619; histone H3-K9 deacetylation
GO:2000111; positive regulation of macrophage apoptotic process
GO:2000270; negative regulation of fibroblast apoptotic process
GO:2000480; negative regulation of cAMP-dependent protein kinase activity
GO:2000481; positive regulation of cAMP-dependent protein kinase activity
GO:2000505; regulation of energy homeostasis
GO:2000614; positive regulation of thyroid-stimulating hormone secretion
GO:2000619; negative regulation of histone H4-K16 acetylation
GO:2000655; negative regulation of cellular response to testosterone stimulus
GO:2000757; negative regulation of peptidyl-lysine acetylation
GO:2000773; negative regulation of cellular senescence
GO:2000774; positive regulation of cellular senescence

Cellular component:

GO:0000790; nuclear chromatin
GO:0005634; nucleus
GO:0005635; nuclear envelope
GO:0005637; nuclear inner membrane
GO:0005654; nucleoplasm
GO:0005677; chromatin silencing complex
GO:0005719; nuclear euchromatin
GO:0005720; nuclear heterochromatin
GO:0005730; nucleolus
GO:0005737; cytoplasm
GO:0005739; mitochondrion
GO:0016605; PML body
GO:0030424; axon
GO:0030426; growth cone
GO:0033553; rDNA heterochromatin
GO:0035098; ESC/E(Z) complex

Function:

GO:0001046; core promoter sequence-specific DNA binding
GO:0001077; transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
GO:0002039; p53 binding
GO:0003714; transcription corepressor activity
GO:0003950; NAD+ ADP-ribosyltransferase activity
GO:0004407; histone deacetylase activity
GO:0005515; protein binding
GO:0008022; protein C-terminus binding
GO:0008134; transcription factor binding
GO:0017136; NAD-dependent histone deacetylase activity
GO:0019213; deacetylase activity
GO:0019899; enzyme binding
GO:0033558; protein deacetylase activity
GO:0034979; NAD-dependent protein deacetylase activity
GO:0035257; nuclear hormone receptor binding
GO:0042393; histone binding
GO:0042802; identical protein binding
GO:0043398; HLH domain binding
GO:0043422; protein kinase B binding
GO:0043425; bHLH transcription factor binding
GO:0046872; metal ion binding
GO:0046969; NAD-dependent histone deacetylase activity (H3-K9 specific)
GO:0051019; mitogen-activated protein kinase binding
GO:0070403; NAD+ binding
GO:1990254; keratin filament binding

Hide GO terms

Protein-protein interacting partners in GenAge