PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.
PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases.
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DOI：
10.1016/j.celrep.2015.07.047
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发表时间：
2015-09-01
期刊：
影响因子：
8.8
通讯作者：
Alexander RW
中科院分区：
文献类型：
--
作者：
Xiong S;Patrushev N;Forouzandeh F;Hilenski L;Alexander RW
细胞衰老和机体衰老易导致与年龄相关的慢性疾病，如神经退行性疾病、代谢疾病和心血管疾病。这些疾病的出现是由于氧化/亲电应激、炎症、线粒体功能障碍、DNA损伤和端粒功能障碍和缩短。对机械联系的理解不完全。在此，我们发现，过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1α）的消融加速血管老化和动脉粥样硬化，与端粒功能障碍和缩短以及DNA损伤一致。PGC-1α缺失可降低端粒酶逆转录酶（TERT）的表达和活性，并增加p53的水平。PGC-1α的异位表达共激活TERT转录，并逆转端粒功能障碍和DNA损伤。此外，α-硫辛酸（ALA），一种非脂溶性线粒体辅因子，上调PGC-1α依赖性TERT和细胞保护性Nrf-2介导的抗氧化剂/亲电响应元件（ARE/ERE）信号级联，并抵消高脂饮食诱导的年龄依赖性动脉病。这些结果说明了PGC-1α在改善衰老，衰老和相关慢性疾病中的关键重要性，并可能为涉及亲电子特异性的新治疗方法提供信息。
Cellular senescence and organismal aging predispose age-related chronic diseases such as neurodegenerative, metabolic and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Herein, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular aging and atherosclerosis coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT), and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription, and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA), a non-dispensable mitochondrial cofactor, up-regulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE) signaling cascades, and counteracts high-fat diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity.