Affinage

SIRT1

NAD-dependent protein deacetylase sirtuin-1 · UniProt Q96EB6

Round 2 corrected
Length
747 aa
Mass
81.7 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT1 is a nuclear NAD⁺-dependent class III protein deacetylase that couples cellular metabolic state to chromatin remodeling, transcription factor activity, DNA repair, autophagy, and circadian clock function by deacetylating both histone (H3, H4K16) and non-histone substrates. Key non-histone substrates include p53 (K382), FOXO1/3a, NF-κB RelA/p65 (K310), PGC-1α, PPARα, LXRα/β (K432/K433), RORγt, Ku70, APE1, Atg5/7/8, eNOS, STAT3, and MFN1, through which SIRT1 regulates apoptosis, gluconeogenesis, fatty acid oxidation, mitochondrial biogenesis, inflammation, Th17 differentiation, base excision repair, and autophagy (PMID:11672523, PMID:14976264, PMID:15152190, PMID:15744310, PMID:18296641, PMID:25918343, PMID:18662547). SIRT1 enzymatic activity is controlled by NAD⁺ availability (indirectly regulated by AMPK), phosphorylation by cyclin B/Cdk1 and JNK1, sumoylation promoted by HDAC4, binding of the activator AROS and the inhibitor DBC1, and transcriptional/post-transcriptional regulation including miR-34a-mediated repression and autophagic degradation via LC3 during senescence (PMID:19262508, PMID:19107194, PMID:17964266, PMID:18755897, PMID:32989246). SIRT1 associates with the CLOCK:BMAL1 complex at circadian promoters, deacetylates BMAL1 and PER2, and is essential for high-amplitude circadian transcription, thereby linking NAD⁺ metabolism to the molecular clock (PMID:18662547, PMID:18662546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    The identification of SIRT1 as an NAD-dependent deacetylase that targets p53 at K382 established its enzymatic mechanism and linked it to apoptosis regulation, answering whether the yeast Sir2 longevity mechanism was conserved in mammals.

    Evidence In vitro deacetylase assay, co-IP, catalytic mutant analysis in human cells by two independent groups

    PMID:11672522 PMID:11672523

    Open questions at the time
    • Crystal structure of SIRT1–p53 complex not yet resolved
    • Physiological context of p53 deacetylation in vivo not addressed
  2. 2002 High

    Demonstration that nicotinamide noncompetitively inhibits SIRT1 by blocking NAD⁺ hydrolysis established the first mechanistic model for endogenous feedback regulation of SIRT1 catalytic activity.

    Evidence Kinetic analysis of recombinant SIRT1 with corroborating yeast genetics

    PMID:12297502

    Open questions at the time
    • In vivo relevance of nicotinamide concentrations for SIRT1 inhibition not established
    • Structural basis of nicotinamide binding pocket not resolved at that time
  3. 2004 High

    Rapid expansion of the SIRT1 substrate repertoire to include FOXO3a, NF-κB RelA/p65, and Ku70 revealed that SIRT1 is not merely a p53 deacetylase but a broad stress-responsive signaling node controlling apoptosis, inflammation, and DNA damage responses.

    Evidence In vitro deacetylase assays, co-IPs, ChIP, functional apoptosis/reporter assays, caloric restriction models across multiple labs

    PMID:14976264 PMID:14980222 PMID:15152190 PMID:15205477

    Open questions at the time
    • Substrate selectivity determinants unknown
    • How SIRT1 discriminates among competing substrates in vivo not resolved
  4. 2004 High

    Discovery that SIRT1 represses PPARγ target genes in adipocytes via NCoR/SMRT recruitment, and that Sirt1 haploinsufficient mice have defective fat mobilization, established SIRT1 as a transcriptional co-repressor in metabolic regulation.

    Evidence ChIP, siRNA knockdown, Sirt1⁺/⁻ mouse fasting experiments, adipogenesis assay

    PMID:15175761

    Open questions at the time
    • Full spectrum of SIRT1-regulated metabolic genes in adipose not mapped
    • Whether SIRT1 deacetylates PPARγ directly was not shown
  5. 2005 High

    Identification of PGC-1α as a direct SIRT1 substrate with site-specific deacetylation connected SIRT1 to hepatic gluconeogenesis and mitochondrial gene regulation, answering how caloric restriction signals converge on metabolic gene expression.

    Evidence In vitro deacetylase assay, domain mutagenesis, primary hepatocyte and fasting liver experiments

    PMID:15716268 PMID:15744310

    Open questions at the time
    • Specific lysine residues on PGC-1α targeted by SIRT1 not fully mapped
    • Relative contributions of SIRT1 vs. other deacetylases to PGC-1α regulation in different tissues unclear
  6. 2005 High

    The finding that resveratrol activation of SIRT1 was fluorophore-dependent challenged the direct activator model and raised questions about the physiological relevance of small-molecule SIRT1 activation.

    Evidence Systematic comparison of fluorophore-labeled vs. unlabeled peptide substrates in in vitro deacetylase assays

    PMID:15749705

    Open questions at the time
    • Whether resveratrol activates SIRT1 on full-length protein substrates remained debated
    • In vivo mechanism of resveratrol-SIRT1 axis not fully reconciled
  7. 2007 High

    Discovery of AROS as a direct SIRT1 activator and identification of LXRα/β as SIRT1 substrates at defined lysines expanded understanding of SIRT1 regulation and placed it in cholesterol/lipid homeostasis.

    Evidence Co-IP, in vitro deacetylase assay, AROS-binding-defective SIRT1 mutant, LXR K432 mutagenesis, in vivo target gene expression

    PMID:17936707 PMID:17964266

    Open questions at the time
    • Relative contribution of AROS vs. DBC1 in different tissues not determined
    • Full physiological impact of SIRT1-LXR axis on reverse cholesterol transport not assessed
  8. 2008 High

    Three major biological roles were simultaneously established: SIRT1 promotes autophagy by deacetylating Atg5/7/8, entrains the circadian clock via the CLOCK:BMAL1 complex and PER2 deacetylation, and is subject to miR-34a-mediated post-transcriptional repression creating a p53–miR-34a–SIRT1 feedback loop.

    Evidence SIRT1 KO MEFs with reconstitution, ChIP at circadian promoters, liver-specific KO mice, 3′ UTR reporter assay, genetic epistasis in p53-null cells

    PMID:18296641 PMID:18662546 PMID:18662547 PMID:18755897

    Open questions at the time
    • Relative importance of SIRT1 autophagy regulation vs. other autophagy deacetylases unclear
    • Whether SIRT1 circadian role is secondary to NAMPT/NAD⁺ oscillations not resolved
  9. 2008 High

    Mapping of 13 in vivo phosphorylation sites on SIRT1 and demonstration that cyclin B/Cdk1-mediated phosphorylation at T530/S540 is required for cell cycle progression established post-translational regulation as a key layer of SIRT1 control.

    Evidence Mass spectrometry, in vitro Cdk1 kinase assay, phosphosite mutant cell cycle analysis

    PMID:19107194

    Open questions at the time
    • Functional significance of most of the 13 phosphosites not individually characterized
    • Phosphatase(s) responsible for SIRT1 dephosphorylation not identified
  10. 2009 High

    The finding that AMPK enhances SIRT1 activity by raising cellular NAD⁺ rather than by direct phosphorylation provided the mechanistic basis for metabolic convergence of AMPK and SIRT1 signaling on PGC-1α and FOXO targets.

    Evidence NAD⁺ measurements, deacetylation assays, pharmacological and genetic AMPK manipulation in skeletal muscle

    PMID:19262508

    Open questions at the time
    • Whether AMPK–NAD⁺–SIRT1 axis operates identically across all tissues not established
    • Quantitative relationship between NAD⁺ fluctuations and SIRT1 activity thresholds unknown
  11. 2009 High

    Hepatocyte-specific SIRT1 deletion causing steatosis, inflammation, and ER stress under high-fat diet demonstrated that SIRT1-PPARα-PGC-1α cooperation is essential for hepatic lipid homeostasis in vivo.

    Evidence Liver-specific Cre-lox SIRT1 KO mice, co-IP of SIRT1-PPARα, gene expression, histopathology

    PMID:19356714

    Open questions at the time
    • Whether SIRT1 directly deacetylates PPARα or acts solely as a PGC-1α co-regulator not fully resolved
    • Contribution of hepatic SIRT1 loss to systemic metabolic phenotypes not fully dissected
  12. 2010 High

    Demonstration that SIRT1 deacetylates eNOS downstream of AMPK-mediated phosphorylation, and that SIRT1 KO mice show impaired cognition and synaptic plasticity, extended SIRT1 functions to vascular biology and neuronal physiology.

    Evidence Co-IP, eNOS acetylation assay with AMPKα2 KO mice, SIRT1 KO mouse behavioral and electrophysiological analysis

    PMID:20479254 PMID:20660252

    Open questions at the time
    • Direct neuronal substrates mediating synaptic plasticity defects not identified
    • Whether eNOS deacetylation is the primary mechanism of SIRT1 vascular protection not established
  13. 2015 High

    Identification of RORγt as a SIRT1 deacetylation substrate that enhances Th17 differentiation resolved how SIRT1 participates in adaptive immune regulation, with conditional T cell KO suppressing autoimmune disease.

    Evidence Co-IP, in vitro deacetylase assay, T cell-specific Sirt1 KO mice, EAE model, hematopoietic chimeras

    PMID:25918343

    Open questions at the time
    • Whether SIRT1-RORγt axis operates in human Th17 biology not directly shown
    • Mechanism by which deacetylation increases RORγt activity not structurally resolved
  14. 2020 High

    Discovery that SIRT1 is itself degraded by macroautophagy via LC3 recognition during senescence and aging revealed a self-limiting feedback mechanism explaining age-dependent SIRT1 decline.

    Evidence Autophagy inhibitors, LC3 interaction assay, subcellular fractionation, aged mouse tissues, human CD8⁺CD28⁻ T cells

    PMID:32989246

    Open questions at the time
    • Specific LC3-interacting region (LIR motif) on SIRT1 not mapped
    • Whether pharmacological autophagy inhibition can restore SIRT1 levels and reverse aging phenotypes not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and quantitative model integrating how SIRT1 discriminates among its >20 known substrates in different cellular contexts, and how its multiple post-translational modifications (phosphorylation, sumoylation) combinatorially tune substrate selectivity, remains unresolved.
  • No full-length SIRT1 structure with native substrate bound
  • Quantitative kinetic parameters for most substrates lacking
  • How tissue-specific SIRT1 functions are programmed despite ubiquitous expression is mechanistically unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0140110 transcription regulator activity 6 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 2 R-HSA-9909396 Circadian clock 2 R-HSA-1640170 Cell Cycle 1
Partners
AROSCLOCKFOXO3PPARAPPARGC1ARELATP53XRCC6
Complex memberships
CLOCK:BMAL1 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SIRT1 (hSIR2) functions as an NAD-dependent deacetylase that binds p53 and deacetylates it specifically at Lys382, reducing p53 transcriptional activity; a catalytically inactive SIRT1 mutant potentiates p53-dependent apoptosis and radiosensitivity. Co-immunoprecipitation, in vitro deacetylase assay, site-specific mutagenesis, overexpression in human cells Cell High 11672522 11672523
2002 Nicotinamide noncompetitively inhibits both yeast Sir2 and human SIRT1 deacetylase activity in vitro (IC50 < 50 µM), acting by binding a conserved pocket adjacent to NAD+ and blocking NAD+ hydrolysis. In vitro deacetylase assay, kinetic analysis, yeast genetic experiments The Journal of Biological Chemistry High 12297502
2003 Resveratrol activates SIRT1 by lowering its Michaelis constant for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In vitro sirtuin activity assay, yeast lifespan assay, cell survival assay with SIRT1 overexpression Nature High 12939617
2004 SIRT1 physically interacts with FOXO3 (and FOXO3a) in response to oxidative stress and deacetylates FOXO3 in vitro and in cells; SIRT1 increases FOXO3's ability to induce cell cycle arrest and stress resistance while inhibiting FOXO3's pro-apoptotic activity. Co-immunoprecipitation, in vitro deacetylase assay, loss-of-function/gain-of-function in mammalian cells Science High 14976264
2004 SIRT1 deacetylates and represses the forkhead transcription factor FOXO3a and other mammalian forkhead factors, paralleling its effect on p53, thereby reducing forkhead-dependent apoptosis. Co-immunoprecipitation, in vitro deacetylase assay, transcriptional reporter assay, apoptosis assay Cell High 14980222
2004 SIRT1 physically interacts with the RelA/p65 subunit of NF-κB and inhibits NF-κB-dependent transcription by deacetylating RelA/p65 at lysine 310, thereby sensitizing cells to TNFα-induced apoptosis. Co-immunoprecipitation, chromatin immunoprecipitation, in vitro deacetylase assay, transcriptional reporter assay The EMBO Journal High 15152190
2004 Caloric restriction induces SIRT1 expression in rat tissues and human cells; SIRT1 deacetylates Ku70, causing it to sequester the pro-apoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptosis. In vitro and in vivo CR experiments, co-immunoprecipitation, subcellular fractionation, apoptosis assay Science High 15205477
2004 Sirt1 binds to and represses PPARγ target genes in white adipocytes by docking with co-repressors NCoR and SMRT, promoting fat mobilization; Sirt1+/− mice show compromised fatty acid mobilization upon fasting, and Sirt1 overexpression attenuates adipogenesis. Co-immunoprecipitation, ChIP, siRNA knockdown, Sirt1+/− mouse model, adipogenesis assay Nature High 15175761
2005 SIRT1 directly interacts with and deacetylates PGC-1α in vitro and in vivo; a single amino acid mutation in SIRT1's ADP-ribosyltransferase domain abolishes the SIRT1–PGC-1α interaction while preserving SIRT1 binding to p53 and Foxo3a. Co-immunoprecipitation, in vitro deacetylase assay, site-directed mutagenesis, NAD-dependent activity assay The Journal of Biological Chemistry High 15716268
2005 SIRT1 forms a complex with PGC-1α and deacetylates PGC-1α at specific lysine residues in an NAD+-dependent manner in liver during fasting; SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α but does not regulate PGC-1α effects on mitochondrial genes. Co-immunoprecipitation, in vitro NAD+-dependent deacetylase assay, adenoviral overexpression, primary hepatocyte studies Nature High 15744310
2005 Among the seven human SIRT proteins, SIRT1 is localized in the nucleus, shows in vitro deacetylase activity on histone H4 and p53 peptides, and is the primary deacetylase for cellular p53 (not shared by SIRT2–7); overexpression of any single SIRT does not extend replicative lifespan in normal human fibroblasts. Subcellular fractionation/immunofluorescence, in vitro peptide deacetylase assay, siRNA/overexpression, replicative lifespan assay Molecular Biology of the Cell High 16079181
2005 Resveratrol activation of SIRT1 in vitro is entirely dependent on the presence of a covalently attached fluorophore on the substrate peptide; without fluorophore, resveratrol does not activate SIRT1 against native peptides, suggesting allosteric modulation is fluorophore-dependent. In vitro deacetylase assay with fluorophore-labeled and unlabeled peptide substrates, substrate competition studies, structural modeling The Journal of Biological Chemistry High 15749705
2006 E2F1 induces SIRT1 expression at the transcriptional level; SIRT1 binds to E2F1 and inhibits E2F1 transcriptional and apoptotic activities, forming a negative feedback loop; SIRT1 knockdown increases E2F1-dependent apoptosis and cellular sensitivity to etoposide. Co-immunoprecipitation, siRNA knockdown, reporter assay, apoptosis assay Nature Cell Biology High 16892051
2006 Resveratrol treatment of mice activates SIRT1, decreases PGC-1α acetylation and increases PGC-1α activity, inducing oxidative phosphorylation and mitochondrial biogenesis genes; resveratrol has no effect in SIRT1−/− MEFs, placing SIRT1 upstream of PGC-1α in the pathway. Mouse metabolic phenotyping, gene expression analysis, SIRT1−/− MEFs as genetic control, PGC-1α acetylation assay Cell High 17112576
2007 SIRT1 interacts with LXRα and LXRβ and promotes their deacetylation at a single conserved lysine (K432 in LXRα, K433 in LXRβ) adjacent to AF2; deacetylation promotes subsequent LXR ubiquitination and upregulation of targets including ABCA1; K432 mutation eliminates LXRα activation by SIRT1. Co-immunoprecipitation, in vitro deacetylase assay, site-directed mutagenesis, in vivo LXR target gene expression Molecular Cell High 17936707
2007 AROS (Active Regulator of SIRT1) is a nuclear protein that directly binds SIRT1 and enhances SIRT1-mediated deacetylation of p53 both in vitro and in vivo; an AROS-binding-defective SIRT1 mutant abolishes AROS-dependent p53 inactivation; AROS knockdown increases p21WAF1 expression and apoptosis. Co-immunoprecipitation, in vitro deacetylase assay, site-directed mutagenesis, antisense knockdown, cell cycle and apoptosis assays Molecular Cell High 17964266
2007 SIRT1 physically complexes with the DNA repair protein Ku70 and deacetylates it; catalytically inactive SIRT1 fails to deacetylate Ku70 or enhance DNA strand-break repair, indicating that SIRT1 deacetylase activity is required for its DNA repair-promoting function. Co-immunoprecipitation, dominant-negative SIRT1 mutant, comet assay (DNA repair), acetylation immunoblot Experimental & Molecular Medicine Medium 17334224
2007 SIRT1 is upregulated in mouse models of Alzheimer's disease and ALS; in cell-based models, SIRT1 promotes neuronal survival and reduces acetylation of PGC-1α and p53; lentiviral SIRT1 injection in hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. In vivo mouse models (p25 transgenic, SOD1 ALS), lentiviral SIRT1 overexpression, acetylation immunoblot, neuronal survival assay The EMBO Journal High 17581637
2008 miR-34a inhibits SIRT1 expression through a miR-34a binding site in the 3' UTR of SIRT1; miR-34a suppression of SIRT1 increases acetylated p53, upregulates p21 and PUMA, and leads to apoptosis in p53-WT colon cancer cells but not in p53-null cells, establishing a p53→miR-34a→SIRT1→p53 positive feedback loop. 3' UTR reporter assay, siRNA/miRNA overexpression, acetylation immunoblot, apoptosis assay in p53-WT vs. p53-null cells Proceedings of the National Academy of Sciences High 18755897
2008 SIRT1 has a role in neurogenesis: oxidative stress and inflammation bias neuronal stem cell differentiation toward astrocytes by modulating Sirt1 activity, linking a longevity gene to neuronal stem cell fate decisions. Neuronal stem cell differentiation assay with SIRT1 modulation Nature Cell Biology Medium 18379594
2008 SIRT1 regulates autophagy: transient SIRT1 overexpression stimulates basal autophagy; SIRT1−/− MEFs fail to fully activate autophagy under starvation; wild-type but not deacetylase-inactive SIRT1 restores autophagy; SIRT1 forms a molecular complex with Atg5, Atg7, and Atg8 and directly deacetylates them in an NAD-dependent fashion in vitro. SIRT1 KO MEFs, reconstitution with WT vs. catalytic mutant SIRT1, co-immunoprecipitation with autophagy proteins, in vitro deacetylase assay, autophagy flux assay Proceedings of the National Academy of Sciences High 18296641
2008 SIRT1 is an NAD+-dependent HDAC that associates with the CLOCK:BMAL1 chromatin complex at circadian promoters; genetic ablation or pharmacological inhibition of SIRT1 disrupts circadian transcription and acetylation of H3 and BMAL1; SIRT1 promotes deacetylation and degradation of PER2, connecting cellular NAD+ metabolism to the circadian clock. ChIP, SIRT1 KO cells/liver-specific mutant mice, pharmacological inhibition, PER2 acetylation and stability assays Cell High 18662546 18662547
2008 SIRT1 associates with the CLOCK:BMAL1 complex and is recruited to circadian promoters; it is required for high-magnitude circadian transcription of Bmal1, Rorgamma, Per2, and Cry1; SIRT1 promotes deacetylation and degradation of PER2, with NAD+ dependence linking cellular metabolism to clockwork. ChIP, SIRT1 KO cells, pharmacological inhibition, PER2 deacetylation assay Cell High 18662546
2008 SIRT1 phosphorylation by cyclin B/Cdk1 at Thr530 and Ser540 is required for normal cell cycle progression; dephosphorylation of SIRT1 by phosphatases reduces its NAD+-dependent deacetylase activity; 13 in vivo phosphorylation sites on SIRT1 were identified by mass spectrometry. Mass spectrometry phosphosite mapping, in vitro phosphatase assay, cyclin B/Cdk1 kinase assay, cell cycle analysis with phospho-site mutants PLoS One High 19107194
2008 Sirt1 deficiency in mice markedly attenuates spermatogenesis: numbers of mature sperm and spermatogenic precursors are significantly reduced, DNA damage in sperm is elevated, and genes involved in spermatogenesis and protein sumoylation are dysregulated; Sirt1-deficient sperm show reduced fertilization efficiency. Sirt1 KO mouse model, sperm counting, TUNEL assay, microarray gene expression, in vitro fertilization PLoS One Medium 18270565
2009 AMPK enhances SIRT1 activity by increasing cellular NAD+ levels (not by direct phosphorylation), resulting in deacetylation of SIRT1 targets PGC-1α, FOXO1, and FOXO3a in mouse skeletal muscle; this NAD+-mediated AMPK–SIRT1 axis explains convergent metabolic effects of both kinases. Skeletal muscle gene expression, NAD+ measurement, deacetylation assays, pharmacological and genetic AMPK manipulation Nature High 19262508
2009 JNK1 phosphorylates SIRT1 at Ser27, Ser47, and Thr530 under oxidative stress conditions; this phosphorylation increases SIRT1 nuclear localization and enzymatic activity; notably, JNK1-phosphorylated SIRT1 shows substrate specificity: it deacetylates histone H3 but not p53. Co-immunoprecipitation of endogenous proteins, in vitro kinase assay, phospho-site mutagenesis, deacetylase activity assay, nuclear localization imaging PLoS One Medium 20027304
2009 SIRT1 associates with APE1 (apurinic/apyrimidinic endonuclease-1), deacetylates APE1 at lysines 6 and 7 in vitro and in vivo; SIRT1 knockdown increases cellular abasic DNA content and sensitizes cells to genotoxic death; SIRT1 activation promotes APE1 binding to XRCC1 and enhances BER pathway activity. Co-immunoprecipitation, in vitro deacetylase assay, siRNA knockdown, abasic site quantification, BER activity assay Nucleic Acids Research Medium 19934257
2009 Hepatocyte-specific SIRT1 deletion impairs PPARα signaling and fatty acid β-oxidation; SIRT1 interacts with PPARα and is required for PGC-1α coactivation of PPARα; liver-specific SIRT1 KO mice on high-fat diet develop hepatic steatosis, inflammation, and ER stress. Hepatocyte-specific Cre-lox SIRT1 KO mice, co-immunoprecipitation, gene expression, adenoviral SIRT1 overexpression, histopathology Cell Metabolism High 19356714
2010 Laminar shear stress increases SIRT1 level and activity in endothelial cells; SIRT1 associates with eNOS and deacetylates it; AMPK-mediated phosphorylation of eNOS at Ser-633/1177 is required to prime SIRT1-induced eNOS deacetylation, enhancing NO production; AMPKα2−/− mice show increased eNOS acetylation in aorta. Co-immunoprecipitation, eNOS acetylation assay, AMPK inhibitor/eNOS phospho-site mutants, AMPKα2 KO mice, flow experiments Proceedings of the National Academy of Sciences High 20479254
2010 SIRT1 is essential for normal cognitive function and synaptic plasticity: SIRT1 KO mice show impaired learning, memory, classical conditioning, and spatial learning; these deficits correlate with defects in synaptic plasticity, decreased dendritic branching, reduced ERK1/2 phosphorylation, and altered expression of hippocampal genes involved in synaptic function, lipid metabolism, and myelination. SIRT1 KO mouse model, behavioral paradigms (fear conditioning, Morris water maze), LTP electrophysiology, Golgi staining of dendrites, gene expression The Journal of Neuroscience High 20660252
2011 SIRT1 deacetylates FOXO1 in pancreatic β-cells; SIRT1 activity determines whether FoxO1 drives a protective (GADD45α-mediated DNA repair) or proapoptotic (PUMA induction, caspase-3 cleavage) response to nitric oxide; SIRT1 inhibitors switch FoxO1-dependent protection to apoptosis. SIRT1 pharmacological inhibition, FoxO1 localization (nuclear translocation imaging), GADD45α/PUMA expression assay, caspase-3 assay in β-cells The Journal of Biological Chemistry Medium 21196578
2011 SIRT1 and SIRT3 deacetylate homologous substrates in their respective compartments: SIRT1 deacetylates AceCS1 and HMGCS1 in the cytoplasm, while SIRT3 deacetylates AceCS2 and HMGCS2 in mitochondria, revealing a pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3. In vitro deacetylase assay, phylogenetic analysis, fractionation Aging Medium 21701047
2015 SIRT1 deacetylates RORγt, the master transcription factor of Th17 cells, increasing RORγt transcriptional activity and enhancing Th17 cell generation; T cell-specific Sirt1 deletion suppresses Th17 differentiation and is protective in a mouse model of multiple sclerosis. Co-immunoprecipitation, in vitro deacetylase assay, T cell-specific Sirt1 KO mice, Th17 differentiation assay, EAE mouse model, hematopoietic chimera analysis The Journal of Experimental Medicine High 25918343
2016 SIRT1 stabilizes mitofusin 1 (MFN1) by deacetylating it; TIP60 acetyltransferase promotes MFN1 degradation, while SIRT1 deacetylase counteracts this; SIRT1 knockdown reduces MFN1 levels and mitochondrial elongation, while SIRT1 overexpression increases MFN1; under hypoxia, SIRT1 and MFN1 accumulate and mitochondria elongate. siRNA knockdown, SIRT1 overexpression, in vitro acetylation assay with TIP60 and SIRT1, immunoprecipitation, mitochondrial morphology imaging Cellular Signalling Medium 28669827
2016 HDAC4 stabilizes SIRT1 protein by enhancing its sumoylation, thereby increasing SIRT1 protein levels and delaying cellular senescence; HDAC4 knockdown leads to premature senescence in human fibroblasts. Co-immunoprecipitation, sumoylation assay, HDAC4 overexpression/knockdown, senescence assay (SA-β-gal) Clinical and Experimental Pharmacology & Physiology Medium 26414199
2017 SIRT1 activates fetal hemoglobin (γ-globin/HBG) gene expression by binding to the β-globin LCR and HBG promoters, promoting LCR-to-HBG promoter looping, increasing RNA Pol II and H4K16Ac at HBG promoter, and suppressing BCL11A, KLF1, HDAC1, and HDAC2 expression; small molecule SIRT1 activators SRT2104 and SRT1720 reactivate silenced HBG in adult erythroblasts. ChIP, chromosome conformation capture (looping assay), SIRT1 knockdown/overexpression, small molecule activators in primary human erythroblasts American Journal of Hematology Medium 28776729
2018 SIRT1 represses NF-κB-driven transcription of the AIM2 gene in cervical cancer cells by destabilizing RELB mRNA; SIRT1 knockdown derepresses AIM2 inflammasome-mediated pyroptosis, demonstrating a pro-tumorigenic role of SIRT1 through innate immune suppression. SIRT1 siRNA knockdown, SIRT1 restoration, AIM2 promoter/NF-κB reporter assay, RELB mRNA stability assay, pyroptosis assay, xenograft model Oncogene Medium 29844574
2019 SIRT1 mediates increased mitochondrial oxidative phosphorylation in CML leukemia stem cells (LSCs) via deacetylation of PGC-1α; genetic SIRT1 deletion in transgenic CML mice reduces LSC maintenance and enhances tyrosine kinase inhibitor efficacy; mitochondrial alterations are BCR-ABL kinase-independent. Conditional SIRT1 KO in CML transgenic mice, Seahorse metabolic profiling, PGC-1α acetylation assay, LSC functional assays The Journal of Clinical Investigation High 31180336
2019 SIRT1 deacetylates STAT3, leading to STAT3 destabilization and degradation, thereby repressing FGB (fibrinogen beta chain) expression and inhibiting RCC tumor growth; overexpression of SIRT1 suppresses RCC proliferation in vitro and in vivo through this SIRT1-STAT3-FGB axis. Co-immunoprecipitation, STAT3 acetylation/ubiquitination assay, SIRT1 overexpression, luciferase reporter (FGB as STAT3 target), in vivo xenograft Experimental Cell Research Medium 31201813
2019 SIRT1 protects hypoxic cardiomyocytes via two pathways: (1) promoting autophagic flux through AMPK activation (blocked by compound C), and (2) reducing apoptosis through IRE1α pathway inhibition. Adenoviral SIRT1 overexpression/knockdown in H9C2 cells, pharmacological activator/inhibitor (SRT1720/EX-527), AMPK inhibitor (compound C), apoptosis assay (TUNEL, Annexin V), autophagic flux assay, in vivo hypoxic mouse model International Journal of Molecular Medicine Medium 30864731
2020 Macroautophagy mediates SIRT1 protein downregulation during senescence and ageing: nuclear SIRT1 is recognized as an autophagy substrate via the autophagy protein LC3, and is subjected to cytoplasmic autophagosome-lysosome degradation; this mechanism operates in multiple immune tissues in aged mice and in aged human CD8+CD28− T cells. Autophagy pathway inhibitors, LC3 interaction assay, subcellular fractionation, aged mouse tissue analysis, human T cell aging model Nature Cell Biology High 32989246
2021 ADNP and SIRT1 form a protein complex with two key interaction sites: one at the microtubule end-binding proteins EB1/EB3 and Tau level, and one at the DNA/chromatin site involving YY1, HDAC2, with sex- and age-dependent regulation of histone modifications; ADNP-SIRT1-EB1 correlation is specifically abolished in Alzheimer's and Parkinson's disease brain regions. Co-immunoprecipitation, single-cell RNA/protein expression, gene expression correlation analysis, postmortem brain tissue analysis Molecular Psychiatry Medium 33967268

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 3314 17112576
2003 Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2874 12939617
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2004 Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science (New York, N.Y.) 2764 14976264
2009 AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2664 19262508
2005 Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2628 15744310
2004 Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. The EMBO journal 2318 15152190
2001 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2263 11672523
2008 TEAD mediates YAP-dependent gene induction and growth control. Genes & development 2100 18579750
2001 Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 1845 11672522
2004 Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 1624 15175761
2004 Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science (New York, N.Y.) 1596 15205477
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2008 A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America 1238 18296641
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2004 Mammalian SIRT1 represses forkhead transcription factors. Cell 1156 14980222
2000 Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochemical and biophysical research communications 1155 10873683
2008 miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences of the United States of America 1137 18755897
2005 Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Molecular biology of the cell 1127 16079181
2008 The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 1120 18662547
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2008 SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 1088 18662546
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2006 SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 975 16959573
2009 Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell metabolism 914 19356714
2005 SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. The Journal of biological chemistry 894 15716268
2007 SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. The EMBO journal 870 17581637
2005 Mechanism of human SIRT1 activation by resveratrol. The Journal of biological chemistry 859 15749705
2002 Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. The Journal of biological chemistry 834 12297502
2010 AMPK and SIRT1: a long-standing partnership? American journal of physiology. Endocrinology and metabolism 733 20103737
2016 Sirt1 and the Mitochondria. Molecules and cells 595 26831453
2022 Regulation of SIRT1 and Its Roles in Inflammation. Frontiers in immunology 557 35359990
2007 SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Molecular cell 529 17936707
2020 SIRT1 and aging related signaling pathways. Mechanisms of ageing and development 519 32084459
2010 Regulation of SIRT1 in cellular functions: role of polyphenols. Archives of biochemistry and biophysics 514 20450879
2010 SIRT1 is essential for normal cognitive function and synaptic plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 449 20660252
2020 SIRT1 is downregulated by autophagy in senescence and ageing. Nature cell biology 386 32989246
2009 MiR-34, SIRT1 and p53: the feedback loop. Cell cycle (Georgetown, Tex.) 385 19221490
2008 How does SIRT1 affect metabolism, senescence and cancer? Nature reviews. Cancer 374 19132007
2020 Role of Silent Information Regulator 1 (SIRT1) in Regulating Oxidative Stress and Inflammation. Inflammation 372 32410071
2006 Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nature cell biology 372 16892051
2007 Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Molecular cell 330 17964266
2007 SIRT1 promotes DNA repair activity and deacetylation of Ku70. Experimental & molecular medicine 288 17334224
2004 The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends in cell biology 287 15308206
2017 Emerging roles of SIRT1 in fatty liver diseases. International journal of biological sciences 286 28808418
2009 SIRT1, is it a tumor promoter or tumor suppressor? International journal of biological sciences 281 19173036
2008 Phosphorylation regulates SIRT1 function. PloS one 229 19107194
2010 Shear stress, SIRT1, and vascular homeostasis. Proceedings of the National Academy of Sciences of the United States of America 223 20479254
2009 JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PloS one 221 20027304
2012 Negative regulation of inflammation by SIRT1. Pharmacological research 205 23098819
2008 The ups and downs of SIRT1. Trends in biochemical sciences 201 18805010
2011 Protective roles of SIRT1 in atherosclerosis. Cell cycle (Georgetown, Tex.) 192 21293192
2007 Function of the SIRT1 protein deacetylase in cancer. Biotechnology journal 187 17806102
2019 Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress. International journal of molecular medicine 169 30864731
2012 MicroRNA Regulation of SIRT1. Frontiers in physiology 159 22479251
2009 SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic acids research 150 19934257
2015 SIRT1 deacetylates RORγt and enhances Th17 cell generation. The Journal of experimental medicine 129 25918343
2013 The ways and means that fine tune Sirt1 activity. Trends in biochemical sciences 127 23394938
2008 Sirt1 deficiency attenuates spermatogenesis and germ cell function. PloS one 127 18270565
2009 Biochemical effects of SIRT1 activators. Biochimica et biophysica acta 117 19897059
2021 Interplay between oxidative stress, SIRT1, reproductive and metabolic functions. Current research in physiology 115 34746831
2012 Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochemical pharmacology 110 22796566
2017 The role of SIRT1 in diabetic retinopathy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 100 29091865
2012 Targeting cardiovascular disease with novel SIRT1 pathways. Future cardiology 99 22185448
2015 Multifaceted Modulation of SIRT1 in Cancer and Inflammation. Critical reviews in oncogenesis 98 25746104
2021 SIRT1-FOXOs activity regulates diabetic complications. Pharmacological research 94 34856334
2010 Controlling SIRT1 expression by microRNAs in health and metabolic disease. Aging 91 20689156
2011 SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging 89 21701047
2018 Role and Possible Mechanisms of Sirt1 in Depression. Oxidative medicine and cellular longevity 87 29643977
2014 Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut. Mucosal immunology 86 24850427
2009 Metabolic benefits from Sirt1 and Sirt1 activators. Current opinion in clinical nutrition and metabolic care 83 19474719
2018 Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense. Oncogene 82 29844574
2018 Sirt1 Antisense Long Noncoding RNA Promotes Cardiomyocyte Proliferation by Enhancing the Stability of Sirt1. Journal of the American Heart Association 82 30608184
2014 The Role of SIRT1 in Diabetic Kidney Disease. Frontiers in endocrinology 80 25346724
2013 Brain activation of SIRT1: role in neuropathology. Molecular neurobiology 78 23615921
2014 P53 and Sirt1: routes of metabolism and genome stability. Biochemical pharmacology 73 25218422
2020 SIRT1 Regulation in Ageing and Obesity. Mechanisms of ageing and development 72 32320732
2011 Expression and role of SIRT1 in hepatocellular carcinoma. Oncology reports 72 21567102
2023 SIRT1/SREBPs-mediated regulation of lipid metabolism. Pharmacological research 70 38070792
2008 SIRT1: roles in aging and cancer. BMB reports 70 19017485
2017 The NAD+/PARP1/SIRT1 Axis in Aging. Rejuvenation research 67 28537485
2013 Regulation of SIRT1 by microRNAs. Molecules and cells 67 24213676
2011 FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide. The Journal of biological chemistry 62 21196578
2019 P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy. Biochimica et biophysica acta. Molecular cell research 59 30959066
2019 SIRT1 regulates metabolism and leukemogenic potential in CML stem cells. The Journal of clinical investigation 59 31180336
2011 Sirtuin 1 (SIRT1) and steroid hormone receptor activity in cancer. The Journal of endocrinology 58 22159506
2010 C/EBPalpha regulates SIRT1 expression during adipogenesis. Cell research 58 20157332
2021 Trending topics of SIRT1 in tumorigenicity. Biochimica et biophysica acta. General subjects 56 34147543
2013 Stress Inducibility of SIRT1 and Its Role in Cytoprotection and Cancer. Genes & cancer 55 24020008
2015 Role of SIRT1 in autoimmune demyelination and neurodegeneration. Immunologic research 54 25281273
2022 Nutraceutical activation of Sirt1: a review. Open heart 52 36522127
2014 Clinicopathological significance of SIRT1 expression in colorectal adenocarcinoma. Medical oncology (Northwood, London, England) 52 24816737
2024 SIRT1, resveratrol and aging. Frontiers in genetics 51 38784035
2019 CD38 Deficiency Alleviates D-Galactose-Induced Myocardial Cell Senescence Through NAD+/Sirt1 Signaling Pathway. Frontiers in physiology 50 31551807
2017 Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. Cellular signalling 50 28669827
2014 SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis. Oncology reports 50 25270091
2024 SIRT1: Harnessing multiple pathways to hinder NAFLD. Pharmacological research 48 38527697
2014 Dual role of SIRT1 in UVB-induced skin tumorigenesis. Oncogene 47 24441046
2022 Resveratrol-like Compounds as SIRT1 Activators. International journal of molecular sciences 46 36499460
2016 SIRT1 prevents hyperuricemia via the PGC-1α/PPARγ-ABCG2 pathway. Endocrine 46 27022940
2009 Cellular regulation of SIRT1. Current pharmaceutical design 46 19149601
2008 Neurogenesis directed by Sirt1. Nature cell biology 46 18379594
2021 Circ-SIRT1 inhibits cardiac hypertrophy via activating SIRT1 to promote autophagy. Cell death & disease 45 34759275
2017 Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development. Current biology : CB 45 28162896
2023 The Role of Sirtuin 1 (SIRT1) in Neurodegeneration. Cureus 44 37456463
2019 Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα. Biochemical and biophysical research communications 43 30928103
2017 SIRT1 Regulates the Chemoresistance and Invasiveness of Ovarian Carcinoma Cells. Translational oncology 42 28667895
2013 Cross-talk between SIRT1 and p66Shc in vascular diseases. Trends in cardiovascular medicine 42 23499302
2015 SIRT1 and Kidney Function. Kidney diseases (Basel, Switzerland) 41 27536685
2021 Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation. Molecular psychiatry 40 33967268
2011 The role of SirT1 in muscle mitochondrial turnover. Mitochondrion 40 21406254
2013 Towards elucidating the role of SirT1 in osteoarthritis. Frontiers in bioscience (Landmark edition) 39 23276927
2012 Metabolic actions of hypothalamic SIRT1. Trends in endocrinology and metabolism: TEM 39 22382036
2016 HDAC4 stabilizes SIRT1 via sumoylation SIRT1 to delay cellular senescence. Clinical and experimental pharmacology & physiology 37 26414199
2010 Sirt1's systemic protective roles and its promise as a target in antiaging medicine. Translational research : the journal of laboratory and clinical medicine 37 21497775
2020 Impact of circadian disruption on health; SIRT1 and Telomeres. DNA repair 36 33038659
2017 The Role of Sirt1 in Epileptogenesis. eNeuro 36 28197553
2017 SIRT1 activates the expression of fetal hemoglobin genes. American journal of hematology 36 28776729
2017 Resveratrol Attenuates Microglial Activation via SIRT1-SOCS1 Pathway. Evidence-based complementary and alternative medicine : eCAM 36 28781601
2011 The role of SIRT1 in tumorigenesis. North American journal of medicine & science 36 22180829
2015 Expression of SIRT1 and SIRT3 varies according to age in mice. Anatomy & cell biology 35 25806122
2013 Roles of SIRT1 in leukemogenesis. Current opinion in hematology 35 23519155
2012 Expression of SIRT1 and DBC1 in Gastric Adenocarcinoma. Korean journal of pathology 35 23323102
2019 SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3. Experimental cell research 34 31201813
2009 Physiological and pathophysiological functions of SIRT1. Mini reviews in medicinal chemistry 34 19275731
2022 Irisin enhances longevity by boosting SIRT1, AMPK, autophagy and telomerase. Expert reviews in molecular medicine 32 36503597
2014 Linking DNA damage, NAD(+)/SIRT1, and aging. Cell metabolism 31 25440052