NF-κB inhibition delays DNA damage–induced senescence and aging in mice
Jeremy S. Tilstra, … , Laura J. Niedernhofer, Paul D. Robbins
Jeremy S. Tilstra, … , Laura J. Niedernhofer, Paul D. Robbins
Published June 18, 2012
Citation Information: J Clin Invest. 2012;122(7):2601-2612. https://doi.org/10.1172/JCI45785.
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Research Article Aging

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

Abstract

The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB–activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

Authors

Jeremy S. Tilstra, Andria R. Robinson, Jin Wang, Siobhán Q. Gregg, Cheryl L. Clauson, Daniel P. Reay, Luigi A. Nasto, Claudette M. St Croix, Arvydas Usas, Nam Vo, Johnny Huard, Paula R. Clemens, Donna B. Stolz, Denis C. Guttridge, Simon C. Watkins, George A. Garinis, Yinsheng Wang, Laura J. Niedernhofer, Paul D. Robbins

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Figure 5

Inhibition of NF-κB reduces cellular senescence in vitro and in vivo.

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Inhibition of NF-κB reduces cellular senescence in vitro and in vivo. (A...
(A) Proliferation of WT (black; n = 4), Ercc1–/– (red; n = 3), Ercc1–/–p65+/– (purple; n = 1) and Ercc1–/–p65–/– (orange; n = 3) congenic primary MEFs grown at 20% O2 for several passages. Ercc1–/– MEFs grew slower than WT MEFs, while Ercc1–/–p65–/– MEFs showed better growth compared with that of Ercc1–/– MEFs. (B) γH2AX staining (red) of passage 5 WT, Ercc1–/–, and Ercc1–/–p65–/– primary MEFs grown at 20% O2. Nuclei were counterstained with DAPI (blue; original magnification, ×20). The histogram indicates the percentage of cells positive for γH2AX foci. (C) SA β-gal staining of liver sections from 10-week-old control, Ercc1–/Δ, and Ercc1–/Δp65+/– mice (original magnification, ×40). The histogram indicates the percentage of SA β-gal–positive cells from 5 images from at least 9 mice per genotype. Values denote the mean ± SEM. *P < 0.05, Tukey-Kramer test. (D) Immunodetection of p16 in liver extracts of 19-week-old untreated Ercc1–/Δ and NBD-treated Ercc1–/Δ mice.