심홍석 (The University of Texas MD Anderson Cancer Center) | 한빛사논문 > 한빛사

한빛사논문

조회340

The University of Texas MD Anderson Cancer Center

Cell, Available online 21 June 2024 | https://doi.org/10.1016/j.cell.2024.05.048 TERT activation targets DNA methylation and multiple aging hallmarks

Hong Seok Shim ¹, Jonathan Iaconelli ², Xiaoying Shang ¹, Jiexi Li ¹, Zheng D. Lan ¹, Shan Jiang ³, Kayla Nutsch ², Brittney B. Beyer ², Luke L. Lairson ², Adam T. Boutin ¹, Michael J. Bollong ², Peter G. Schultz ², Ronald A. DePinho ^1,4

¹Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

²Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA

³Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

⁴Lead contact

Corresponding author: Ronald A. DePinho

Abstract

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) 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 TERT 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 p16 ^INK4a 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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-07-01)
연구진국외 연구진
분야

댓글 작성 로그인

CV 열람하기

연락처 보기