Loss of <i>Nfkb1</i> leads to early onset aging

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

doi:doi:10.18632/aging.100702

Research Paper Volume 6, Issue 11 pp 931—942

Loss of Nfkb1 leads to early onset aging

Giovanna M. Bernal^{1,

,}, Joshua S. Wahlstrom^{1,

,}, Clayton D. Crawley^1,, Kirk E. Cahill^1,, Peter Pytel^2,, Hua Liang^3,, Shijun Kang^1,, Ralph R. Weichselbaum^3,, Bakhtiar Yamini^1,,

¹ Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL 60637, USA
² Department of Pathology, University of Chicago, Chicago, IL 60637, USA
³ Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA

* Equal contribution https://doi.org/10.18632/aging.100702
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Bernal GM, Wahlstrom JS, Crawley CD, Cahill KE, Pytel P, Liang H, Kang S, Weichselbaum RR, Yamini B, . Loss of Nfkb1 leads to early onset aging. Aging (Albany NY). 2014; 6:931-942. https://doi.org/10.18632/aging.100702

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Provider: 
        TY  - JOUR
        AU  - Bernal, Giovanna M. 
        AU  - Wahlstrom, Joshua S. 
        AU  - Crawley, Clayton D. 
        AU  - Cahill, Kirk E. 
        AU  - Pytel, Peter 
        AU  - Liang, Hua 
        AU  - Kang, Shijun 
        AU  - Weichselbaum, Ralph R. 
        AU  - Yamini, Bakhtiar 
        TI  - Loss of <i>Nfkb1</i> leads to early onset aging
        JO  - 
        JA  - Aging (Albany NY)
        VL  - 6
        IS  - 11
        PB  - 
        SN  - 
        UR  - https://doi.org/10.18632/aging.100702
        DO  - 10.18632/aging.100702
        SP  - 931
        EP  - 942
        PY  - 
        AB  - NF-(B is a major regulator of age-dependent gene expression and the p50/NF-(B1 subunit is an integral modulator of NF-(B 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-(B pathway and mammalian aging.
        ER  -

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Abstract

NF-(B is a major regulator of age-dependent gene expression and the p50/NF-(B1 subunit is an integral modulator of NF-(B 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-(B pathway and mammalian aging.