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TERT activation targets DNA methylation and multiple aging hallmarks.

Hong Seok Shim1, Jonathan Iaconelli2, Xiaoying Shang1

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

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|June 22, 2024
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Summary

Low telomerase reverse transcriptase (TERT) activity drives aging. A novel compound activates TERT, promoting telomere synthesis and reducing aging signs in cells and mice without toxicity.

Keywords:
adult neurogenesiscognitionepigeneticsinflammationp16(INK4a)senescencetelomerasetelomere

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Area of Science:

  • Molecular Biology
  • Gerontology
  • Biochemistry

Background:

  • Telomere shortening and reduced telomerase reverse transcriptase (TERT) activity are linked to aging and age-related diseases.
  • TERT plays a dual role in telomere maintenance and as a transcriptional co-regulator in aging processes.

Purpose of the Study:

  • To identify and characterize a compound that activates TERT transcription.
  • To evaluate the therapeutic potential of TERT activation in mitigating aging hallmarks and associated pathologies.

Main Methods:

  • Identification of a TERT activator compound (TAC) that modulates the MEK/ERK/AP-1 signaling pathway.
  • Assessment of TAC effects on TERT levels, telomere synthesis, cellular senescence, and inflammatory markers in human cells and aged mice.
  • Evaluation of TAC's impact on neuroinflammation, neurogenesis, and cognitive function in vivo.

Main Results:

  • TAC successfully upregulated TERT transcription and telomere synthesis in primary human cells and aged mice.
  • TAC treatment reduced cellular senescence, inflammatory cytokines, and silenced p16INK4a expression via DNMT3B-mediated hypermethylation.
  • In the brain, TAC alleviated neuroinflammation, enhanced neurotrophic factors, stimulated neurogenesis, and preserved cognitive function without inducing toxicity or increasing cancer risk.

Conclusions:

  • Physiological TERT activation is a viable strategy for combating multiple aging hallmarks.
  • The identified TERT activator compound shows preclinical promise for treating age-associated diseases and promoting healthier aging.