Circular RNA Telomerase Reverses Endothelial Senescence in Progeria

Area of Science:

• Molecular Biology
• Cellular Aging
• Genetics

Background:

• Telomere shortening acts as a cellular clock, contributing to aging and age-related diseases.
• Telomerase, particularly human TERT, can reverse telomere erosion but its mRNA form has a short half-life.
• Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by cellular senescence.

Purpose of the Study:

• To investigate the efficacy of TERT circular RNA (circRNA) in extending telomere length and reversing senescence.
• To compare the effectiveness of TERT circRNA versus TERT mRNA in HGPS endothelial cells.

Main Methods:

• Transient transfection of HGPS endothelial cells with TERT circRNA or TERT mRNA.
• Quantitative fluorescence in situ hybridization to measure telomere length.
• Assays for senescence markers (β-gal, Progerin, p16, p21), inflammatory markers (IL-1B, IL-6, IL-8, MCP1), DNA damage (γH2AX), NO production, proliferation, angiogenesis, LDL uptake, and mitochondrial function (ROS, membrane potential).

Main Results:

• A single TERT circRNA transfection significantly extended telomere length more effectively than TERT mRNA.
• TERT circRNA markedly reduced senescence markers, inflammatory cytokines, and DNA damage in HGPS cells.
• TERT circRNA restored endothelial cell function, including NO production, proliferation, angiogenesis, and normalized mitochondrial activity.

Conclusions:

• TERT circRNA is a more effective and sustained method for telomere maintenance and senescence reversal than TERT mRNA.
• TERT circRNA demonstrates significant therapeutic potential for Hutchinson-Gilford progeria syndrome and other aging-related conditions.