A multidimensional systems biology analysis of cellular senescence in aging and disease

Roberto A. Avelar, Javier Gómez Ortega, Robi Tacutu, Eleanor J. Tyler, Dominic Bennett, Paolo Binetti, Arie Budovsky, Kasit Chatsirisupachai, Emily Johnson, Alex Murray, Samuel Shields, Daniela Tejada-Martinez, Daniel Thornton, Vadim E. Fraifeld, Cleo L. Bishop, João Pedro De Magalhães

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

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.

Original languageEnglish
Article number91
JournalGenome Biology
Volume21
Issue number1
DOIs
StatePublished - 7 Apr 2020

Keywords

  • Biogerontology
  • Cancer
  • Genetics
  • Longevity
  • Transcriptome

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Fingerprint

Dive into the research topics of 'A multidimensional systems biology analysis of cellular senescence in aging and disease'. Together they form a unique fingerprint.

Cite this