Loss of Nfkb1 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 +8 more
- Vol. 6, Iss: 11, pp 931-943
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TLDR
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.read more
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Methods to Quantify the NF-κB Pathway During Senescence.
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References
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Journal ArticleDOI
Cellular senescence: when bad things happen to good cells
TL;DR: Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
Journal ArticleDOI
Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders
Darren J. Baker,Tobias Wijshake,Tamar Tchkonia,Nathan K. LeBrasseur,Bennett G. Childs,Bart van de Sluis,James L. Kirkland,Jan M. van Deursen +7 more
TL;DR: Data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
Journal ArticleDOI
A DNA damage checkpoint response in telomere-initiated senescence
Fabrizio d'Adda di Fagagna,Philip Michael Reaper,Lorena Clay-Farrace,Heike Fiegler,Philippa Carr,Thomas von Zglinicki,Gabriele Saretzki,Nigel P. Carter,Stephen P. Jackson +8 more
TL;DR: It is proposed that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.
Journal ArticleDOI
Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors
Judith Campisi,Judith Campisi +1 more
TL;DR: The senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Journal ArticleDOI
The essence of senescence
TL;DR: The various features of cellular senescence are reviewed and their contribution to tumor suppression is discussed and the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo are highlighted.
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