title: Aging increases cell-to-cell transcriptional variability upon immune stimulation.
abstract: Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4+T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Celia Pilar
authors.initials: CP
authors.lastname: Martinez-Jimenez
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Nils
authors.initials: N
authors.lastname: Eling
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Hung-Chang
authors.initials: HC
authors.lastname: Chen
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.|MRC Biostatistics Unit, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
authors.forename: Catalina A
authors.initials: CA
authors.lastname: Vallejos
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Aleksandra A
authors.initials: AA
authors.lastname: Kolodziejczyk
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Connor
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Lovorka
authors.initials: L
authors.lastname: Stojic
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Rayner
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Michael J T
authors.initials: MJT
authors.lastname: Stubbington
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Maike
authors.initials: M
authors.lastname: de la Roche
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Marioni
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Duncan T
authors.initials: DT
authors.lastname: Odom
mesh_terms: D000375:Aging / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D014644:Genetic Variation; D007156:Immunologic Memory / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D059467:Transcriptome
chemical_list: D011948:Receptors, Antigen, T-Cell