Integrative single‑cell transcriptomics and translational profiling to delineate heterogeneity in cellular senescence
Integrative single‑cell transcriptomics and translational profiling to delineate heterogeneity in cellular senescence
As we age, some cells enter a state called cellular senescence, in which they stop dividing and undergo changes in gene activity. Because senescent cells are rare and vary between tissues, identifying them remains difficult.
This thesis of Abdullah Altulea introduces SenFlag, a gene signature that detects senescent cells in single-cell RNA sequencing data. This technology measures gene activity in cells to distinguish cell populations within a tissue. SenFlag defines cell-cycle arrest as the central hallmark of senescence, rather than relying on heterogeneous, context-dependent inflammatory or secretory markers. It combines reduced expression of genes involved in cell division and DNA organization with increased expression of cell-cycle inhibitors and lysosomal genes. Across mouse and human tissues, SenFlag identified senescent cells that became more common with age, particularly in epithelial and endothelial populations.
The thesis examines how translation regulation differs between forms of senescence. Analysis of RNA sequencing and ribosome profiling data revealed patterns of ribosome stalling and regulatory RNA elements depending on how senescence was induced, showing that senescence does not follow one uniform molecular program.
Lifestyle factors, including exercise and diet, have been proposed to influence senescent-cell burden and aging. This thesis examines this relationship through lifespan data from more than 95,000 international athletes. Different sports showed different associations with lifespan, although the observational design cannot establish cause and effect.
Finally, macrophage migration inhibitory factor, or MIF, was increased in SenFlag-positive cells and was the only gene shared across several senescence signatures, motivating a review of its role in aging and age-related disease.