Replicative senescence induction in single cells is not predicted by telomere length, dysfunction, or oxidation

Area of Science:

• Cell Biology
• Aging Research
• Genomics

Background:

• Cellular senescence, characterized by irreversible cell cycle arrest, contributes to age-related diseases.
• Current understanding suggests telomere dysfunction, including shortening, DNA damage response (DDR), and oxidation, drives replicative senescence.
• Aging primary human fibroblasts exhibit increased time in a non-cycling state and elevated senescence biomarkers.

Purpose of the Study:

• To investigate the reliability of telomere features as single-cell biomarkers for replicative senescence.
• To correlate cell-cycle dynamics with specific telomere characteristics in aging human fibroblasts.
• To identify robust cellular markers for senescence induction.

Main Methods:

• Utilized a high-throughput, long-term time-lapse imaging workflow.
• Integrated confocal imaging to map cell-cycle dynamics to telomere features within the same cell.
• Analyzed telomere length, DNA damage response (DDR), and telomere oxidation in aging primary human fibroblasts.

Main Results:

• Telomere length and DDR did not reliably distinguish cycling from non-cycling cells across different ages.
• Telomere oxidation was not associated with cell-cycle withdrawal in senescent cells.
• Lysosomal content, cell size, genomic architecture, and p21 expression were more reliable indicators of senescence induction.

Conclusions:

• Replicative senescence represents a complex state transition, not solely driven by telomere dysfunction.
• Current measurable telomere features show weak correlation with senescence.
• Lysosomal content, cell size, genomic architecture, and p21 are more dependable biomarkers for senescence.