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Abstract Introduction Understanding changes in cell identity in cancer and ageing is of great importance. In this work, we analyzed how gene expression changes in human tissues are associated with tissue specificity during cancer and ageing using transcriptome data from TCGA and GTEx. Results We found significant downregulation of tissue-specific genes during ageing in 40% of the tissues analyzed, which suggests loss of tissue identity with age. For most cancer types, we have noted a consistent pattern of downregulation in genes that are specific to the tissue from which the tumor originated. Moreover, we observed in cancer an activation of genes not usually expressed in the tissue of origin as well as an upregulation of genes specific to other tissues. These patterns in cancer were associated with patient survival. The age of the patient, however, did not influence these patterns. Conclusion We identified loss of cellular identity in 40% of the tissues analysed during human ageing, and a clear pattern in cancer, where during tumorigenesis cells express genes specific to other organs while suppressing the expression of genes from their original tissue. The loss of cellular identity observed in cancer is associated with prognosis and is not influenced by age, suggesting that it is a crucial stage in carcinogenesis.

The retinal pigment epithelium (RPE) and the choroid are ocular tissues with fundamental roles in supporting neuroretinal function. The pathogenesis of age-related macular degeneration (AMD), a leading cause of irreversible blindness for which aging is the highest risk factor is closely linked with progressive impairment of various functions of these tissues. Cellular senescence, marked by cell cycle arrest and secretion of proinflammatory factors, is known to be associated with aging and has been proposed as a potential driver of AMD. Here, we investigated the role played by intercellular communication in the RPE/choroid within the context of aging, senescence and AMD. We inferred cell–cell interactions in the RPE/choroid by applying CellChat and scDiffCom on a publicly available scRNA-seq dataset from three human donors with and without AMD. We identified age-regulated ligand and receptor genes by using limma on a separate publicly available bulk microarray dataset providing RPE/choroid samples at multiple time points. Cellular senescence was investigated by assigning a score to each cell and each sample of these scRNA-seq and microarray datasets, respectively, based on the expression of key signature genes determined by a previous senescence meta-analysis. We identified VEGF-, BMP-and tenascin-mediated pathways supporting some of the strongest cell–cell interactions between RPE cells, fibroblasts and choroidal endothelial cells and as strong intercellular communication pathways related to both aging and senescence. Their signaling strength was enhanced between subpopulations of cells having high senescence scores. Predominant ligands of these pathways were upregulated with age whereas predominant receptors were downregulated. Globally, we also observed that cells from AMD samples presented slightly bigger senescence scores than normal cells and that the senescence score positively correlated with age in bulk samples (R = 0.26, value of p

Our understanding of the age-related molecular alterations in cancer is still limited. Here, the authors perform a pan-cancer analysis of age-associated genomic, transcriptomic, and epigenetic alterations, linking age-related gene expression changes to age-related DNA methylation alterations

Abstract Background Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. Results We develop CellAge ( http://genomics.senescence.info/cells ), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence. Conclusions Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.