Abstract
BackgroundCellular 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.ResultsWe 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.ConclusionsOverall, 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.
Highlights
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
We have performed a meta-analysis to derive a molecular signature of replicative cellular senescence (CS) and found 526 overexpressed and 734 underexpressed genes [32]
Using the database for annotation, visualization and integrated discovery—DAVID Version 6.8 [35, 36], we found that genes in CellAge are enriched with several clusters associated with Protein Kinase Activity, Transcription Regulation, DNA-binding, DNA damage repair, and Cell cycle regulation in cancer
Summary
A permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. In the 1960s, Leonard Hayflick and Paul Moorhead demonstrated that human fibroblasts reached a stable proliferative growth arrest between their fortieth and sixtieth divisions [1] Such cells would enter an altered state of “replicative senescence,” subsisting in a nonproliferating, metabolically active phase with a distinct vacuolated morphology [2]. Mice expressing transgenic INK-ATTAC, which induces apoptosis of p16-positive senescent cells, have increased lifespan and improved healthspan [14]. It is, no surprise that in recent years gerontology has heavily focused on the prevention or removal of senescent cells as a means to slow or stop aging and related pathologies [15,16,17]
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