Senescent Cell Heterogeneity: Tissue-Dependent Signatures and Age Dynamics Revealed by Human scRNA-Seq Data

It is well established that aging is accompanied by the accumulation of senescent cells across tissues. The triggers inducing cellular senescence are diverse and vary across cell types and organs, underpinning the high diversity of senescence phenotypes within individual cell types as well as at the tissue and organismal levels. Identifying common transcriptional patterns and senescence triggers while accounting for the remarkable diversity of aged and dysfunctional cells is fundamental to developing strategies aimed at reducing senescent cell burden. The aim of this study was to investigate the heterogeneity of human senescent cells across tissues at single-cell transcriptome resolution. We selected publicly available scRNA-seq data from healthy donors for the skin, lungs, small and large intestine, kidneys, and heart. The final dataset comprised 1.5 million cells from six tissues, encompassing 64 annotated cell types across 177 donors aged 15 to 88 years. To identify cell type-specific senescence signatures, we reproduced and adapted the signature identification algorithm underlying the SenePy library. This enabled us to identify de novo genes associated with aging and senescent status within a given dataset. Next, for senescent cells of each cell type, we obtained differentially expressed gene sets and performed gene set enrichment analysis (GSEA) using a broad collection of terms reflecting functional status, metabolic activity, and adaptive responses to various forms of cellular stress. As a result, we identified organ-specific aging features in senescent cells of different cell types. We also assessed the enrichment of antigen presentation pathways and the production of senescence-associated pro-inflammatory factors (SASP) in senescent cells across tissues. Furthermore, our analysis revealed novel tissue-specific patterns of ligand-receptor interactions between senescent cells and their microenvironment.