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

TLDR

Cellular damage, especially DNA damage, is linked to aging and degenerative changes, yet the mechanisms remain unclear; accelerated aging in XFE progeroid syndrome arises from DNA repair defects, and NF‑κB activity rises with age and age‑related chronic disease. The study aimed to test whether NF‑κB mediates aging driven by endogenous DNA damage by measuring its activation in wild‑type and progeroid mice, and to assess if NF‑κB inhibition could mitigate aging phenotypes. The authors measured NF‑κB activation in wild‑type and progeroid mice and used genetic depletion of one p65 allele or IKK inhibition to suppress NF‑κB activity. NF‑κB activation increased stochastically with age in diverse cell types, and reducing NF‑κB activity—by p65 haplo‑deletion or IKK inhibition—delayed progeroid symptoms, lowered oxidative DNA damage, and postponed cellular senescence, demonstrating that DNA damage promotes aging partly through NF‑κB and suggesting therapeutic potential.

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.