Loss of Nfkb1 leads to early onset aging.

Giovanna M Bernal,Bakhtiar Yamini,Joshua S Wahlstrom,Shijun Kang,Kirk E Cahill,Peter Pytel,Ralph R Weichselbaum,Clayton D Crawley,Hua Liang

doi:10.18632/aging.100702

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.

Highlights

Aging is a universal process involving the progressive decline in organ function that eventually leads to organismal death
While the most commonly used Nfkb1-/- mouse is found on the original B6/129 cross background [14], it is well documented that animal strain plays a significant role in lifespan and disease predisposition [16]
Examination of γH2AX foci in both newborn and 12-month old mouse brains demonstrates that, as with mouse embryonic fibroblasts (MEFs), significantly more γH2AX foci are seen in the brains of Nfkb1-/compared to age-matched Nfkb1+/+ animals. These findings indicate that loss of Nfkb1 leads to a decrease in spontaneous apoptosis and an increase in DNA damage signaling, findings that are consistent with the increase in cellular senescence and premature aging seen in Nfkb1-/- cells and animals

Summary

Introduction

Aging is a universal process involving the progressive decline in organ function that eventually leads to organismal death. Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor that has been intimately linked to cellular senescence, DNA damage signaling and organismal aging [8,9,10,11]. NF-κB dimers are retained in the cytoplasm through interaction with inhibitor-κB (IκB) proteins. Activation of IκK leads to IκB protein degradation and subsequent NFκB nuclear translocation. NF-κB dimers regulate genes involved in a wide range of cellular processes. The ubiquitous expression of p50 suggests that this subunit plays a critical role in a broad range of physiological processes. The ubiquitous expression of p50 suggests that this subunit plays a critical role in a broad range of physiological processes. p50 is encoded by the NFKB1 gene and is www.impactaging.com

Methods

Results

Conclusion