Faculty, Staff and Student Publications

Language

English

Publication Date

7-25-2024

Journal

Cell

DOI

10.1016/j.cell.2024.05.048

PMID

38908367

PMCID

PMC11552617

PubMedCentral® Posted Date

7-25-2025

PubMedCentral® Full Text Version

Author MSS

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 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.

Keywords

Telomerase, Humans, Animals, DNA Methylation, Aging, Mice, DNA (Cytosine-5-)-Methyltransferases, Cellular Senescence, Promoter Regions, Genetic, DNA Methyltransferase 3B, Brain, Telomere, Mice, Inbred C57BL, Male, Transcription Factor AP-1, Cyclin-Dependent Kinase Inhibitor p16, Neurogenesis, telomerase, telomere, senescence, inflammation, p16INK4a, epigenetics, adult neurogenesis, cognition

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.