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NF-?B 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-?B, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-?B drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-?B in WT and progeroid model mice. As both WT and progeroid mice aged, NF-?B was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-?B or treatment with a pharmacological inhibitor of the NF-?B-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-?B 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-?B activation. IKK/NF-?B inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

SUBMITTER: Tilstra JS

PROVIDER: S-EPMC3386805 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Tilstra Jeremy S JS Robinson Andria R AR Wang Jin J Gregg Siobhán Q SQ Clauson Cheryl L CL Reay Daniel P DP Nasto Luigi A LA St Croix Claudette M CM Usas Arvydas A Vo Nam N Huard Johnny J Clemens Paula R PR Stolz Donna B DB Guttridge Denis C DC Watkins Simon C SC Garinis George A GA Wang Yinsheng Y Niedernhofer Laura J LJ Robbins Paul D PD

The Journal of clinical investigation 20120618 7

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 da ...[more]

PMID: 22706308

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Project description:Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death, and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs, and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here, we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence, and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair, and senescence. These data confirm on-target activity of statins, although via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as nontoxic radiosensitizers to enhance the benefits of image-guided radiotherapy. Mol Cancer Ther; 17(2); 407-18. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

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NF-?B inhibition delays DNA damage-induced senescence and aging in mice.

Publications

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

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