Insufficient telomerase activity, stemming from low () gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT’s critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

中文翻译：

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TERT 激活针对 DNA 甲基化和多种衰老标志


由于 () 基因转录水平低而导致端粒酶活性不足，导致端粒功能障碍和衰老病理。除了端粒合成中的传统功能外，TERT 还充当衰老和年龄相关疾病关键基因的转录共调节因子。在这里，我们报告了一种通过 MEK/ERK/AP-1 级联上调转录的 TERT 激活剂化合物 (TAC) 的鉴定。在原代人类细胞和自然衰老的小鼠中，TAC 诱导的 TERT 水平升高可促进端粒合成，通过减少细胞衰老和炎症细胞因子来减弱组织衰老标志，并通过上调 DNMT3B 介导的启动子高甲基化来沉默表达。在大脑中，TAC 可以减轻神经炎症，增加神经营养因子，刺激成人神经发生，并保留认知功能，而没有明显的毒性，包括癌症风险。总之，这些发现强调了 TERT 在衰老过程中的关键作用，并为生理学 TERT 激活作为减轻多种衰老特征和相关病理的策略提供了临床前概念证明。