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Abstract:
:NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated (ATM) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that ATM is activated in senescent cells in culture and murine tissues from Ercc1-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of ATM reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent Ercc1-/- MEFs. Ercc1-/Δ mice heterozygous for Atm have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of Ercc1-/∆ mice with the ATM inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the ATM kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.
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最新影响因子:5.955 | 期刊ISSN:1945-4589 | CiteScore: |
出版周期:Monthly | 是否OA:YES | 出版年份:2008 |
期刊官方网址:http://www.aging-us.com/
期刊投稿地址:http://aging.msubmit.net/
自引率:7.40% | 研究方向:CELL BIOLOGY- |
出版地区:UNITED STATES |
SCI期刊coverage:Science Citation Index Expanded(科学引文索引扩展)
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Aging-US
老龄化
大类(学科) | 小类(学科) | 学科排名 |
医学 |
CELL BIOLOGY (细胞生物学) 2区 GERIATRICS & GERONTOLOGY (老年医学) 2区 |
48/190 5/53 |
年度总发文量 | 年度论文发表量 | 年度综述发表量 |
149 | 146 | 3 |
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文献(2015-2017)
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