NF-κB inhibition delays DNA damage-induced senescence and aging in mice
NF-κB inhibition delays DNA damage-induced senescence and aging in mice
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DOI：
10.1172/jci45785
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发表时间：
2012-07-01
影响因子：
15.9
通讯作者：
Robbins, Paul D.
中科院分区：
文献类型：
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作者：
Tilstra, Jeremy S.;Robinson, Andria R.;Robbins, Paul D.
细胞损伤的积累，包括DNA损伤，被认为有助于衰老相关的退行性变化，但损伤如何驱动衰老尚不清楚。XFE类早衰综合征是一种由DNA修复缺陷引起的加速衰老疾病。NF-κ B B是一种由细胞损伤和应激激活的转录因子，随着衰老和与衰老相关的慢性疾病而活性增加。为了确定NF-κ B是否响应于自发的内源性DNA损伤的积累而驱动衰老，我们测量了WT和早衰模型小鼠中NF-κ B的活化。随着WT和早衰小鼠的衰老，NF-κ B在多种细胞类型中被随机激活。基因缺失NF-κ B B的p65亚基的一个等位基因或用NF-κ B激活激酶IKK的药理学抑制剂治疗，延迟了早衰小鼠的年龄相关症状和病理学。此外，抑制NF-κ B可减少氧化性DNA损伤和应激，并延缓细胞衰老。这些结果表明，DNA损伤驱动衰老的机制部分是由于NF-κ B激活。IKK/NF-κ B抑制剂足以减轻这种损伤，并可为加速老化疾病和正常老化相关的退行性变化提供临床获益。
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-kappa B, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-kappa B drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-kappa B in WT and progeroid model mice. As both WT and progeroid mice aged, NF-kappa B was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-kappa B or treatment with a pharmacological inhibitor of the NF-kappa B-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-kappa 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-kappa B activation. IKK/NF-kappa B inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.