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 6

Inhibition of NF-κB reduces oxidative stress and damage in vitro and in vivo.

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Inhibition of NF-κB reduces oxidative stress and damage in vitro and in ...
(A) Ercc1–/– and Ercc1–/–p65–/– passage 6 primary MEFs grown at 20% O2 were stained with DiOC6 (green) to mark mitochondria and MitoSOX (red) to detect mitochondrial superoxide anion (original magnification, ×40). (B) Liver sections from 10-week-old Ercc1–/Δ and Ercc1–/Δp65+/– mice imaged for lipofuscin fluorescence (original magnification, ×20). The histogram indicates the total fluorescent area for 5 images from 3 different mice per genotype calculated using MetaMorph software. (C) The levels of the (5′R) and (5′S) diastereomers of cdG and cdA in nuclear DNA isolated from the livers of 10-week-old control, p65+/–, Ercc1–/Δ, and Ercc1–/Δp65+/– mice. (D) The levels of cdG and cdA in nuclear DNA isolated from the livers of 19-week-old control, untreated Ercc1–/Δ, and 8K-NBD–treated Ercc1–/Δ mice. *P < 0.05, Tukey-Kramer test. Values denote the mean ± SEM (n = 3 per group).