title: Loss of Nfkb1 leads to early onset aging.
abstract: NF-κB is a major regulator of age-dependent gene expression and the p50/NF-κB1 subunit is an integral modulator of NF-κB signaling. Here, we examined Nfkb1-/- mice to investigate the relationship between this subunit and aging. Although Nfkb1-/- mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1-/- animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1-/- MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1-/- MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1-/- animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-κB pathway and mammalian aging.
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Bernal
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Wahlstrom
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Clayton D
authors.initials: CD
authors.lastname: Crawley
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Cahill
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.affiliation: Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Bakhtiar
authors.initials: B
authors.lastname: Yamini
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019588:Aging, Premature; D000818:Animals; D017209:Apoptosis; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D005911:Gliosis; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007738:Kyphosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008136:Longevity; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D013997:Time Factors
chemical_list: D004247:DNA; D006657:Histones; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse; C475961:gamma-H2AX protein, mouse