NF-κB in Aging and Disease

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; Inflammation; NF-κB; Senescence.

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.