Systems approaches to investigate the role of NF-κB signaling in aging

Abstract

The nuclear factor-κB (NF-κB) signaling pathway is one of the most well-studied pathways related to inflammation, and its involvement in aging has attracted considerable attention. As aging is a complex phenomenon and is the result of a multi-step process, the involvement of the NF-κB pathway in aging remains unclear. To elucidate the role of NF-κB in the regulation of aging, different systems biology approaches have been employed. A multi-omics data-driven approach can be used to interpret and clarify unknown mechanisms but cannot generate mechanistic regulatory structures alone. In contrast, combining this approach with a mathematical modeling approach can identify the mechanistics of the phenomena of interest. The development of single-cell technologies has also helped clarify the heterogeneity of the NF-κB response and underlying mechanisms. Here, we review advances in the understanding of the regulation of aging by NF-κB by focusing on omics approaches, single-cell analysis, and mathematical modeling of the NF-κB network.

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

“…Importantly, Klotho suppresses activation of the inflammatory NF-κB pathway ( Buendia et al, 2015 , 2016 ). This pathway plays a key role in initiating immune and/or inflammatory responses mediated by B cells, T cells, macrophages and polymorphonuclear leukocytes (PMLs) ( Haga and Okada, 2022 ; Roberti et al, 2022 ). It also inhibits apoptosis of immune cells and other cell types, while promoting proliferation.…”

Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis

“…The p52 and p50 forms are processed from the precursors p100 and p105, respectively. These precursors are characterized by multiple ankyrin repeat domains and the ability to bind NF-κB dimers [ 6 , 7 ].…”

“…In unstimulated cells, the five related proteins of the NF-κB family form dimers but remain inactive in the cytosol by forming complexes with IκB proteins [ 6 , 7 ]. The binding of ligands to receptors on the cell membrane stimulates the phosphorylation of the NF-κB and IκB complexes by the IKK complex, and the NF-κB dimers (mainly the RelA/p50 heterodimer) are then activated by the degradation of IκB (mainly IκBα) ( Figure 2 ).…”

“…The binding of ligands to receptors on the cell membrane stimulates the phosphorylation of the NF-κB and IκB complexes by the IKK complex, and the NF-κB dimers (mainly the RelA/p50 heterodimer) are then activated by the degradation of IκB (mainly IκBα) ( Figure 2 ). This is called “the classic NF-κB pathway” [ 6 , 7 ]. The IKK complex consists of three subunits, IKKα (also known as IKK1), IKKβ (also known as IKK2), and NEMO ( Figure 2 ).…”

“…Then, a heterodimer of RelB/p52 is formed and translocates into the nucleus. This activation pathway is referred to as “the alternative NF-κB pathway” ( Figure 2 ) [ 6 , 7 ]. RANKL activates both the classic and alternative pathways [ 6 , 7 ].…”