美国德克萨斯大学Ronald A. DePinho课题组发现，TERT激活靶向DNA甲基化和多种衰老特征。该研究于2024年6月21日在线发表于国际一流学术期刊《细胞》。
研究人员报告了一种端粒酶逆转录酶（TERT）激活剂化合物（TAC）的鉴定结果，它能通过MEK/ERK/AP-1级联上调TERT的转录。在原代人体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特征，并通过上调DNMT3B介导的启动子超甲基化来抑制p16INK4a的表达。
在大脑中，TAC可减轻神经炎症，增加神经营养因子，刺激成体神经发生，保护认知功能，且无明显毒性，包括癌症风险。这些发现共同强调了TERT在衰老过程中的关键作用，并提供了生理性TERT激活作为缓解多种衰老特征和相关病症的策略的临床前概念证明。
研究人员表示，端粒酶活性不足源于TERT基因转录量低，导致端粒功能障碍和衰老病症。除了在端粒合成中的传统功能外，TERT还是衰老和年龄相关疾病中关键基因的转录协同调节因子。
附：英文原文
Title: TERT activation targets DNA methylation and multiple aging hallmarks
Author: Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D. Lan, Shan Jiang, Kayla Nutsch, Brittney B. Beyer, Luke L. Lairson, Adam T. Boutin, Michael J. Bollong, Peter G. Schultz, Ronald A. DePinho
Issue&Volume: 2024-06-21
Abstract: Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besidesits traditional function in telomere synthesis, TERT acts as a transcriptional co-regulatorof genes pivotal in aging and age-associated diseases. Here, we report the identificationof a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturallyaged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, bluntstissue aging hallmarks with reduced cellular senescence and inflammatory cytokines,and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In thebrain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulatesadult neurogenesis, and preserves cognitive function without evident toxicity, includingcancer risk. Together, these findings underscore TERT’s critical role in aging processesand provide preclinical proof of concept for physiological TERT activation as a strategyto mitigate multiple aging hallmarks and associated pathologies.
DOI: 10.1016/j.cell.2024.05.048
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00592-0