TERT activation targets DNA methylation and multiple aging hallmarks

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.