TERT激活的目标是DNA甲基化和多个衰老的标志
Hong Seok Shim1, Jonathan Iaconelli2, Xiaoying Shang1
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell
|June 22, 2024
概括
低端粒酶逆转录酶 (TERT) 活性导致衰老. 一种新型化合物激活TERT,促进端粒合成,减少细胞和小鼠的衰老迹象,但没有毒性.
科学领域:
- 分子生物学
- 老年学
- 生物化学
背景情况:
- 端粒缩短和逆转录酶 (TERT) 活性降低与衰老和与年龄相关的疾病有关.
- TERT在端粒维护和老化过程中的转录协调器中起着双重作用.
研究的目的:
- 识别和描述激活TERT转录的化合物.
- 评估TERT激活在缓解衰老特征和相关病理方面的治疗潜力.
主要方法:
- 一种调节MEK/ERK/AP-1信号通路的TERT激活化合物 (TAC) 的鉴定.
- 对人类细胞和老年小鼠的TERT水平,端粒合成,细胞衰老和炎症标志物的TAC影响的评估.
- 在体内评估TAC对神经炎症,神经发生和认知功能的影响.
主要成果:
- 在原始人类细胞和老鼠中,TAC成功上调了TERT转录和端粒合成.
- 通过DNMT3B介导的高甲基化,TAC治疗降低了细胞衰老,炎症性细胞因子,并抑制了p16INK4a的表达.
- 在大脑中,TAC减轻了神经炎症,增强了神经营养因子,刺激了神经发生,并保持了认知功能,而不会引起毒性或增加癌症风险.
结论:
- 生理 TERT 激活是对抗多种衰老特征的一种可行的策略.
- 已发现的TERT激活剂化合物在治疗与年龄相关的疾病和促进健康衰老方面具有前临床意义.
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