NF-κB inhibition delays DNA damage–induced senescence and aging in mice
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
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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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 2

Genetic depletion of the p65 subunit of NF-κB delays aging symptoms and chronic diseases in progeroid Ercc1–/Δ mice.

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Genetic depletion of the p65 subunit of NF-κB delays aging symptoms and ...
(A) EMSA on nuclear extracts from passage 5 WT, Ercc1–/–, Ercc1–/–p65+/–, and Ercc1–/–p65–/– MEFs grown at 20% O2 to measure NF-κB activity after depletion of p65. (B) Ercc1–/Δ and Ercc1–/Δp65+/– mice were evaluated biweekly for the onset of spontaneous symptoms associated with aging. The aging score, which represents the fraction of aging symptoms delayed in a particular mouse compared with its sibling, for littermate pairs of Ercc1–/Δ (red) and Ercc1–/Δp65+/– (orange) mice is a measure of healthspan (11). The mean aging score for each genotype is represented by a black bar. (C) Representative images of Ercc1–/Δ and Ercc1–/Δp65+/– sex-matched littermates at 15 weeks of age. (D) Histopathologic changes in Ercc1–/Δp65+/– and Ercc1–/Δ mice. Liver sections from 10-week-old mice were stained with oil red O to detect neutral lipids (hepatic steatosis; original magnification, ×100). Kidney specimens from 15-week-old mice were stained with H&E to detect proteinaceous renal tubular hyaline casts and glomerulosclerosis (original magnification, ×20). Cerebellar sections from 10-week-old mice were immunostained for GFAP (red), a marker of neurodegeneration. Nuclei were counterstained with DAPI (blue; original magnification, ×40). μCT of the vertebrae to assess bone porosity (for quantification, see Supplemental Figure 3A).