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 3

Pharmacologic inhibition of IKK/NF-κB activation delays aging symptoms and chronic diseases in progeroid Ercc1–/Δ mice.

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Pharmacologic inhibition of IKK/NF-κB activation delays aging symptoms a...
(A) Immunodetection of p-p65 in nuclear extracts of WT or Ercc1–/– primary MEFs treated with 200 μM NBD or untreated (UT). Lamin A/C was used as a loading control. The histogram indicates the level of p-p65 normalized to that of untreated WT cells and corrected for loading. Values denote mean ± SD from 3 experiments. (B) Sibling, sex-matched pairs of Ercc1–/Δ mice were treated with 10 mg/kg 8K-NBD or 8K-mNBD i.p., 3 times per week, beginning at 5 weeks of age. The aging score was calculated between Ercc1–/Δ littermate pairs treated with 8K-mNBD (blue) or 8K-NBD (green). The mean aging score is represented by a black bar (P = 0.003, Student’s t test). (C) Representative images of Ercc1–/Δ mice treated with 8K-NBD or 8K-mNBD peptide at 15 and 19 weeks of age. (D) Histopathologic changes analyzed in tissue sections from 18-week-old Ercc1–/Δ mice treated with 8K-NBD or untreated. Liver sections were stained with oil red O to detect neutral lipids (hepatic steatosis; original magnification, ×100). Kidney specimens were stained with H&E to detect hyaline casts and glomerulosclerosis (original magnification, ×20). Cerebellar sections were immunostained for GFAP (red), a marker of neurodegeneration. Nuclei were counterstained with DAPI (blue; original magnification, ×40). μCT of vertebrae to measure bone porosity (for quantification, see Supplemental Figure 3B).