Loss of Nfkb1 leads to early onset aging
01 Dec 2014-Vol. 6, Iss: 11, pp 931-943
TL;DR: Data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence, and support the strong link between the NF-(B pathway and mammalian 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.
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01 Jan 1981
1,737 citations
TL;DR: It is proposed that controlling senescence-associated inflammation by targeting specific inflammatory mediators may have a beneficial therapeutic effect in treatment of cancer and aging-related diseases.
296 citations
TL;DR: The more that can be understood about the interplay between SCs and the immune system, the faster new interventions may be developed to delay, prevent, or treat age-related dysfunction and the multiple senescence-associated chronic diseases and disorders.
249 citations
TL;DR: The CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency, with a Dutch-Australian CVID-affected family identified a NFKB1 heterozygous splice-donor-site mutation, causing in-frame skipping of exon 8.
Abstract: Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.
193 citations
TL;DR: Recent results reveal that the nuclear factor of kappa light polypeptide gene enhancer in B‐cells 1 (NFKB1) (p105/p50) subunit is an important regulator of NF‐κB activity in vivo, potentially revealing new strategies for targeting this pathway in inflammatory diseases and cancer.
Abstract: The pleiotropic consequences of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) pathway activation result from the combinatorial effects of the five subunits that form the homo- and heterodimeric NF-κB complexes. Although biochemical and gene knockout studies have demonstrated overlapping and distinct functions for these proteins, much is still not known about the mechanisms determining context-dependent functions, the formation of different dimer complexes and transcriptional control in response to diverse stimuli. Here we discuss recent results that reveal that the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) (p105/p50) subunit is an important regulator of NF-κB activity in vivo. These effects are not restricted to being a dimer partner for other NF-κB subunits. Rather p50 homodimers have a critical role as suppressors of the NF-κB response, while the p105 precursor has a variety of NF-κB-independent functions. The importance of Nfkb1 function can be seen in mouse models, where Nfkb1(-/-) mice display increased inflammation and susceptibility to certain forms of DNA damage, leading to cancer, and a rapid ageing phenotype. In humans, low expression of Kip1 ubiquitination-promoting complex 1 (KPC1), a ubiquitin ligase required for p105 to p50 processing, was shown to correlate with a reduction in p50 and glioblastoma incidence. Therefore, while the majority of research in this field has focused on the upstream signalling pathways leading to NF-κB activation or the function of other NF-κB subunits, such as RelA (p65), these data demonstrate a critical role for NFKB1, potentially revealing new strategies for targeting this pathway in inflammatory diseases and cancer.
187 citations
References
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TL;DR: It is shown that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks, and Rapamycin, an inhibitor of mTOR, decreased γH2AX foci formation, leading to activation of atypical DDR without detectableDNA damage.
Abstract: Cellular senescence is currently viewed as a response to DNA damage. In this report, we showed that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks. Nevertheless, senescent cells displayed components of DNA damage response (DDR) such as γH2AX foci and uniform nuclear staining for p-ATM. Importantly, there was no accumulation of 53BP1 in γH2AX foci of senescent cells. Consistently, comet assay failed to detect DNA damage. Rapamycin, an inhibitor of mTOR, which was shown to suppress cellular senescence, decreased γH2AX foci formation. Thus, cellular senescence leads to activation of atypical DDR without detectable DNA damage. Pseudo-DDR may be a marker of general over-activation of senescent cells.
197 citations
"Loss of Nfkb1 leads to early onset ..." refers background in this paper
...Cellular senescence and animal aging have been linked to expression of markers of activation of the DNA damage response including phosphorylation of histone H2AX (γH2AX) [25-27]....
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TL;DR: The age-related increase in redox-sensitive NF-kappaB translocation and binding activities are associated with increased ROS, and further that this transactivation was modulated by the age- related decrease of IkappaBalpha.
189 citations
"Loss of Nfkb1 leads to early onset ..." refers background in this paper
...Although age-associated increase in overall NF-κB binding has been described [28-30, 46-49], a change in dimer composition has not previously been reported....
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Journal Article•
TL;DR: NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage and represents a possible therapeutic target for extending mammalian healthspan.
Abstract: Stochastic damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer's, diabetes and osteoporosis. In mouse models, inhibition of NF-κB leads to delayed onset of age-related symptoms and pathologies. In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan.
188 citations
TL;DR: It is indicated that eukaryotic cells harbor endogenous metabolites that alkylate nuclear DNA at both oxygens and nitrogens and that if the repair of these abasic sites is not initiated by the APN1 AP endonuclease they cause mutations during replication.
Abstract: Three genes that participate in the repair of DNA alkylation damage were recently cloned from Saccharomyces cerevisiae: the MGT1 O6-methylguanine DNA methyltransferase gene, the MAG 3-methyladenine DNA glycosylase gene, and the APN1 apurinic/apyrimidinic (AP) endonuclease gene. Altering the expression levels of these three genes produced significant changes in the S. cerevisiae spontaneous mutation rate. Spontaneous mutation increased in the absence of the MGT1 DNA methyltransferase, presumably because unrepaired, spontaneously produced, O6-alkylguanine lesions mispair during replication. Moreover, changing the ratios of the MAG 3-methyladenine DNA glycosylase and the APN1 AP endonuclease had profound effects on spontaneous mutation rates. In the absence of APN1, the overexpression of MAG increased spontaneous mutation, and the underexpression of MAG decreased spontaneous mutation. We infer that the MAG glycosylase acts upon spontaneously produced 3-alkyladenine and 7-alkylguanine DNA lesions to produce mutagenic abasic sites, and that if the repair of these abasic sites is not initiated by the APN1 AP endonuclease they cause mutations during replication. Our results indicate that eukaryotic cells harbor endogenous metabolites that alkylate nuclear DNA at both oxygens and nitrogens.
177 citations
"Loss of Nfkb1 leads to early onset ..." refers background in this paper
...Given that loss of Nfkb1 leads to decreased apoptosis in response to DNA alkylation damage [15] and that alkylation damage is induced by environmental and endogenous processes [23, 24], we examined spontaneous apoptosis in cultured MEFs....
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TL;DR: Regular exercise‐induced adaptive responses, including attenuation of an increase in ROS production, LIPOX level, NF‐κB activation, and reduced GSH/GSSG ratio, appear to be capable, even in old age, of reducing increases in inflammatory and other detrimental consequences that are often associated with advancing age.
Abstract: The combined effects of aging and regular physical exercise was investigated on the production of reactive oxygen species (ROS), lipid peroxidation, glutathione status, and the activity of nuclear factor-κB (NF-κB) in rat liver. A group of 24 male F344 rats was divided into the following categories: adult control (18 months), adult exercised (18 months), and aged control (28 months) and aged exercised (28 months). The ROS formation increased as a function of age and exercise training decreased the rate of ROS formation in the two age groups. Significant positive correlation was found between ROS production and lipid peroxidation (LIPOX). The reduced glutathione (GSH) level was higher and the oxidized glutathione (GSSG) level lower in exercised groups compared with the sedentary controls (P<0.05). An age-associated increase in NF-κB activity was attenuated by the regular exercise. The content of p50 and p65 subunits of NF-κB increased with age and decreased with exercise training. The content of inhibitory factorκB was inversely related to NF-κB activation. Regular exercise-induced adaptive responses, including attenuation of an increase in ROS production, LIPOX level, NF-κB activation, and reduced GSH/GSSG ratio, appear to be capable, even in old age, of reducing increases in inflammatory and other detrimental consequences that are often associated with advancing age. eactive oxygen species (ROS) are necessary for certain normal biological processes and, at the same time, inevitable potentially harmful products of aerobic metabolism. It has been proven that ROS play an important role in signaling pathways and also regulate transactivation of transcription factors. Hence, ROS appear to be responsible for certain gene expression and cellular responses to internal and external challenges. Nuclear factor κB (NF-κB)
166 citations