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Aging and Disease    2011, Vol. 2 Issue (6) : 449-465     DOI:
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NF-κB in Aging and Disease
Jeremy S. Tilstra1, Cheryl L. Clauson1, Laura J. Niedernhofer1, 2, Paul D. Robbins1, *
1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Abstract  

Stochastic damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer’s, diabetes and osteoporosis. In mouse models, inhibition of NF-κB leads to delayed onset of age-related symptoms and pathologies. In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan.

Keywords Aging      NF-κB      Inflammation      Senescence     
Corresponding Authors: Paul D. Robbins   
Issue Date: 31 October 2014
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Jeremy S. Tilstra
Cheryl L. Clauson
Laura J. Niedernhofer
Paul D. Robbins
Cite this article:   
Jeremy S. Tilstra,Cheryl L. Clauson,Laura J. Niedernhofer, et al. NF-κB in Aging and Disease[J]. Aging and Disease, 2011, 2(6): 449-465.
URL:  
http://www.aginganddisease.org/EN/     OR     http://www.aginganddisease.org/EN/Y2011/V2/I6/449
Figure 1  Schematic Diagram of the NF-κB family members

The NF-κB family members are defined by the n-terminal, Rel Homology Domain (RHD) responsible for DNA binding and dimerization. The p65, c-rel, and RelB family members contain a Transactivation Domain (TAD) which confers positive regulation of gene expression. The transcriptional suppressor family members p52 and p50 contain glycine rich regions (GRR) which are necessary for their proteolytic cleavage and ankyrin repeats similar to those found with IκB proteins, thus acting as cytoplasmic inhibitors of NF-κB. Additionally RelB contains a leucine zipper motif (LZ).

Figure 2  Signaling via the IKK/NF-κB Classical Pathway

The IKK complex (NEMO, IKK1 (IKKα), and IKK2 (IKKβ)) can be activated by numerous stimuli and via shared signaling components. Extracellular receptors bind to their ligands and signal via TRAF/RIP/NIK molecules leading to phosphorylation of IKK subunits, which subsequently phosphorylate IκBα and lead to its ubiquitination and proteosomal degredation. This then releases NF-κB into the nucleus where it acts as a transcription factor. In addition, ATM responds to DNA damage and can also activate the IKK complex. (Figure adapted from [8, 146, 147])

Figure 3  NF-κB is a central regulator in stress response

The NF-κB signaling pathway can be activated by numerous stimuli as listed in the blue boxes (summarized in Subsection entitled: Activation of NF-κB). In response to these different stimuli NF-κB transcriptionally regulates hundreds of genes, the generalized categories of which are listed in the red circles (summarized in subsection entitled: Genes under NF-κB transcriptional control). A compilation of citations with regards to NF-κB activators and transcriptionally regulated genes can be found at (www.nf-kb.org) [7].

Figure 4  Schematic illustration depicting NF-κB as a central factor in pro-aging and longevity pathways

Pro-growth survival pathways known to promote aging phenotypes, specifically Insulin/IGF-1 and mTOR are known to stimulate NF-κB as described. Insulin/IGF-1 acts via two mechanisms, AKT and mTOR signaling, to activate NF-κB. However, through AKT, Insulin/IGF-1 signaling also interacts with known longevity processes by inhibiting FOXO. As with the other known longevity factors and signaling components, SIRT and CR, FOXO inhibits NF-κB signaling as described. Additionally stress/damage pathways known promote age-associated changes including genotoxic stress, ROS, and inflammation also activate NF-κB. Secondary to activation of NF-κB by pro-aging pathways, NF-κB then acts to promote aging related changes by contributing to cellular senescence, SASP, apoptotoic signals and inflammatory responses.

DiseaseStudies in primary cellsStudies with cell lines
Alzheimer’s DiseasePrimary rat neurons [97]Primary rat cerebral granule cells [98]C6 rat glioma cells [95]THP-1 cells [96]Microglial BV2 cells [97]SH-SY5Y cells [98]
Parkinsons’s DiseasePrimary ventral mesencephalic neuron-glia cultures (mouse and rat) [105, 108, 110, 114, 116]Primary ventral mesencephalic neuron-enriched cultures (mouse and rat) [110, 114, 116]Microglia-enriched cultures (mouse and rat) [110, 114]Primary mouse neuron-astroglia cocultures [110]Primary parkin−/− neuronal-enriched mesencephalic primary cultures [115]Primary gp91phox−/− mouse mesencephalic neuron-glia cultures [116]Microglial BV2 cells [113]U937 cells [114]PC-12 cells [119]
Type II Diabetes3T3-L1 adipocytes [123]Fao hepatoma cells [123]
AtherosclerosisMonocyte-derived human macrophages [87]Mouse peripheral blood mononuclear cells [87]Mouse peritoneal macrophages [87]Human atherosclerotic plaque cells [130]Rat artery organoid culture [132]Primary rat coronary arterial endothelial cells [132]Primary rat aortic smooth muscle cells [132]
SarcopeniaC2C12 cells [136]
OsteoporosisC2C12 cells [136]
Table 1  Summary of studies conducted with primary cells or cell lines
DiseaseAnimal models usedHuman patients studied
Alzheimer’s DiseaseapoE−/− mice [94]Sprague-Dawley rat [95]APOE-TR mice [99][93, 101]
Parkinsons’s DiseaseSIV-infected rhesus monkey [107]MPTP treatment in mice [105, 118]MPTP treatment in cynomolgus monkey [111]Paraquat treatment in mice [112][103, 104, 106, 109, 117, 118]
Type II DiabetesZucker fa/fa rats [123]ob/ob mice [123, 125, 126, 128]Ikkβ+/− ob/ob mice [123]Hepatocyte-specific constitutive IKKβ mice [124]db/db; agouti; tubby mice [125]CXCL−/−; KKAy mice [126]TNFα−/−; ob/ob p55−/− p75−/− mice [128][122, 127]
AtherosclerosisapoE−/−; IL-1Ra−/−; IL-1α−/−; IL-1β−/−; IL-4−/−; IL-6−/−; IL-10−/−; IL-12−/−; IL-18−/−; TNFα−/−; IFNγ−/−; Mif−/−; GM-CSF−/− mice reviewed in [131]Fisher 344 rats [132][130]
SarcopeniaMIKK, MISR mice [136]Wistar rats [137]nfkb1−/−; bcl3−/− mice [139]mdx, mdx p65+/−, mdx p50+/− mdx IKKβF/F mice [140][134, 135]
OsteoporosisIKKβ Δ; IKKα−/−; NIK−/−; p50−/− p52−/−; p65−/− TNFR-1−/−; RelB−/−; cRel−/− mice reviewed in: [142]IKKγ dominant-negative mice [145][143, 144]
Table 2  Summary of studies conduected with model animal systems or human patients
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