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TERT activation targets DNA methylation and multiple aging hallmarks
Cell. 2024 Jun 13:S0092-8674(24)00592-0. doi: 10.1016/j.cell.2024.05.048.
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 4
Abstract:
...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 p16INK4a 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.
PMID: 38908367
Tags: cell culture, mice, telomerase