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

TL;DR

This study shows that telomere length, damage, or oxidation do not reliably predict when cells become senescent, suggesting other factors like cell size and p21 are better indicators.

Contribution

The study challenges current models by showing telomere features are weak predictors of single-cell senescence.

Findings

Aging cells increase time in a CDK2-low non-cycling state.

Telomere length and DDR poorly predict senescence proximity.

Lysosomal content and p21 better mark senescence onset.

Abstract

The accumulation of senescent cells during aging contributes to age-associated diseases. Current models posit that replicative senescence is driven by telomere dysfunction, including telomere shortening, telomere-associated DNA damage response (DDR), and telomere oxidation. Here, we first show that aging primary human fibroblasts gradually increase the time spent in a CDK2-low non-cycling state and increase senescence biomarker expression. We then evaluate telomere features as single-cell senescence biomarkers in a workflow linking high-throughput, long-term time-lapse imaging with confocal imaging to map cell-cycle dynamics to telomere features in the same cell. Our results show that telomere length and DDR do not reliably distinguish cycling from non-cycling cells at any age, and that telomere oxidation is not associated with cell-cycle withdrawal. Instead, lysosomal content, cell size, genomic architecture, and p21 more reliably mark senescence induction, depicting replicative senescence as a complex state transition with currently measurable telomere features being weakly correlated with senescence.

•Cells spend increasing amounts of time in a CDK2-low quiescence as they age•Telomere length and oxidation fail to predict senescence proximity•Telomeric DDR foci only weakly predict senescence proximity•Autophagy, cell size, chromatin, and p21 more reliably predict senescence onset

Cells spend increasing amounts of time in a CDK2-low quiescence as they age

Telomere length and oxidation fail to predict senescence proximity

Telomeric DDR foci only weakly predict senescence proximity

Autophagy, cell size, chromatin, and p21 more reliably predict senescence onset

Cell biology; Functional aspects of cell biology; Replicative senescence; Single-cell aging

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