NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
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.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jeremy S
JS
Tilstra
Andria R
AR
Robinson
Jin
J
Wang
Siobhán Q
SQ
Gregg
Cheryl L
CL
Clauson
Daniel P
DP
Reay
Luigi A
LA
Nasto
Claudette M
CM
St Croix
Arvydas
A
Usas
Nam
N
Vo
Johnny
J
Huard
Paula R
PR
Clemens
Donna B
DB
Stolz
Denis C
DC
Guttridge
Simon C
SC
Watkins
George A
GA
Garinis
Yinsheng
Y
Wang
Laura J
LJ
Niedernhofer
Paul D
PD
Robbins
D000375:Aging / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011371:Progeria / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C467063:NBD peptide, mouse; D010455:Peptides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; D004720:Endonucleases; C499360:Ercc1 protein, mouse