Mendelsohn Andrew R, Larrick James W
Panorama Research Institute and Regenerative Sciences Institute , Sunnyvale, California.
Rejuvenation Res. 2015 Oct;18(5):479-83. doi: 10.1089/rej.2015.1780.
Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1α reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1α increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1α and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1α. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC-1α expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance.
随着年龄增长，分裂细胞中的端粒长度缩短，这与人类衰老的病理过程有关，包括心血管和代谢紊乱，其机制是诱导细胞衰老。端粒缩短是由于缺乏维持端粒长度所需的酶——端粒酶。端粒酶逆转录酶（TERT）是端粒酶的蛋白质亚基，仅在包括干细胞和平滑肌细胞在内的一部分成人体细胞中短暂表达。熊及其同事最近的一份报告表明，转录辅因子过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）在维持小鼠TERT表达、预防血管衰老和动脉粥样硬化方面起着关键作用。PGC-1α缺失会降低TERT表达，增加DNA损伤和活性氧（ROS），导致端粒缩短和血管衰老。在动脉粥样硬化的ApoE（-/-）小鼠模型中，PGC-1α的强制表达增加了TERT的表达，延长了端粒，并逆转了基因组DNA损伤、血管衰老和动脉粥样硬化斑块的形成。α硫辛酸（ALA）刺激PGC-1α和TERT的表达，并逆转DNA损伤、血管衰老和动脉粥样硬化，类似于PGC-1α的异位表达。ALA刺激环磷酸腺苷（cAMP）信号传导，进而激活cAMP反应元件结合蛋白（CREB），CREB是PGC-1α表达的辅因子。ALA可能诱导TERT在人类细胞中延长端粒，这表明ALA可能对治疗动脉粥样硬化和其他与衰老相关的疾病有用。然而，需要进一步研究来确定ALA是否在人类细胞中诱导TERT，哪些细胞类型易感，以及这种变化是否具有临床意义。
