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

Tilstra, JS and Robinson, AR and Wang, J and Gregg, SQ and Clauson, CL and Reay, DP and Nasto, LA and St Croix, CM and Usas, A and Vo, N and Huard, J and Clemens, PR and Stolz, DB and Guttridge, DC and Watkins, SC and Garinis, GA and Wang, Y and Niedernhofer, LJ and Robbins, PD (2012) NF-κB inhibition delays DNA damage - Induced senescence and aging in mice. Journal of Clinical Investigation, 122 (7). 2601 - 2612. ISSN 0021-9738

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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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tilstra, JStilstraj@pitt.eduTILSTRAJ
Robinson, AR
Wang, J
Gregg, SQ
Clauson, CL
Reay, DPreayd@pitt.eduREAYD
Nasto, LA
St Croix, CMclaudette.stcroix@pitt.eduCLS13
Usas, A
Vo, Nnvv1@pitt.eduNVV1
Huard, J
Clemens, PRpclemens@pitt.eduPCLEMENS
Stolz, DBdonna.stolz@pitt.eduDSTOLZ
Guttridge, DC
Watkins, SCsimon.watkins@pitt.eduSWATKINS
Garinis, GA
Wang, Y
Niedernhofer, LJniedernh@pitt.eduNIEDERNH
Robbins, PDprobb@pitt.eduPROBB
Centers: Other Centers, Institutes, or Units > Hillman Cancer Center
Other Centers, Institutes, or Units > Stem Cell Research Center
Date: 2 July 2012
Date Type: Publication
Journal or Publication Title: Journal of Clinical Investigation
Volume: 122
Number: 7
Page Range: 2601 - 2612
DOI or Unique Handle: 10.1172/jci45785
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Graduate School of Public Health > Human Genetics
School of Medicine > Cell Biology
School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Neurology
School of Medicine > Orthopaedic Surgery
Refereed: Yes
ISSN: 0021-9738
MeSH Headings: Aging--drug effects; Aging--genetics; Animals; Cell Aging; Cell Nucleus--metabolism; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16--genetics; Cyclin-Dependent Kinase Inhibitor p16--metabolism; DNA Damage; DNA-Binding Proteins--genetics; DNA-Binding Proteins--metabolism; Endonucleases--genetics; Endonucleases--metabolism; Gene Expression Regulation--drug effects; Hepatocytes--drug effects; Hepatocytes--metabolism; Hepatocytes--physiology; I-kappa B Kinase--antagonists & inhibitors; I-kappa B Kinase--metabolism; Mice; Mice, Transgenic; Oxidative Stress; Peptides--pharmacology; Phosphorylation; Progeria--drug therapy; Progeria--pathology; Protein Binding; Signal Transduction; Transcription Factor RelA--genetics; Transcription Factor RelA--metabolism; Transcriptional Activation
Other ID: NLM PMC3386805
PubMed Central ID: PMC3386805
PubMed ID: 22706308
Date Deposited: 31 Mar 2014 15:35
Last Modified: 25 Jan 2019 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/20851

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