Loss of Nfkb1 leads to early onset aging

被引:73
作者
Bernal, Giovanna M. [1 ]
Wahlstrom, Joshua S. [1 ]
Crawley, Clayton D. [1 ]
Cahill, Kirk E. [1 ]
Pytel, Peter [2 ]
Liang, Hua [3 ,4 ]
Kang, Shijun [1 ]
Weichselbaum, Ralph R. [3 ,4 ]
Yamini, Bakhtiar [1 ]
机构
[1] Univ Chicago, Dept Surg, Sect Neurosurg, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA
[4] Univ Chicago, Ludwig Ctr Metastasis Res, Chicago, IL 60637 USA
来源
AGING-US | 2014年 / 6卷 / 11期
关键词
Nfkb1; Aging; CNS gliosis; gamma H2AX; Replicative senescence; NF-KAPPA-B; DNA-DAMAGE RESPONSE; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; CELLULAR SENESCENCE; AGE; P50; DEGENERATION; ACTIVATION; MICE;
D O I
10.18632/aging.100702
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
NF-kappa B is a major regulator of age-dependent gene expression and the p50/NF-kappa B1 subunit is an integral modulator of NF-kappa 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-kappa B pathway and mammalian aging.
引用
收藏
页码:931 / 943
页数:13
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