Integrative Transcriptomic Analysis Decodes the Interplay Between Aging, Senescence, and Cancer

Sep 3, 2025Cancer science

Gene Activity Patterns Reveal How Aging, Cell Aging, and Cancer Are Connected

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Abstract

A total of 648 aging-dependent senescence-associated coregulated modules (SACMs) were identified across 17 tissues, with notable effects on the reproductive systems of both sexes.

may contribute significantly to cancer risk as organisms age.
Single-cell analyses revealed opposing transcriptional profiles between cellular senescence and tumorigenesis.
Aging primarily impacts endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts.
Gene expression changes in endothelial, fibroblast, and epithelial cells often differ between aging and cancer.
Immune cells exhibit decreased self-renewal with aging, which is reversed in epithelial carcinoma.

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Cancer risk increases with age, and may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.

Key numbers

648

Identified

Total number of aging-dependent identified.

76% of 1217

Aging-Related Gene Changes

Percentage of cancer-suppressing genes significantly changing with aging.

86% of 397

Changes

Percentage of significantly changing with aging.

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Integrative Transcriptomic Analysis Decodes the Interplay Between Aging, Senescence, and Cancer

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