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Aging increases cell-to-cell transcriptional variability upon immune stimulation

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Martinez-Jimenez, CP 
Eling, N 
Chen, H-C 
Vallejos, CA 
Kolodziejczyk, AA 


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.



Aging, Animals, CD4-Positive T-Lymphocytes, Cellular Senescence, Genetic Variation, Immunologic Memory, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome

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American Association for the Advancement of Science
European Research Council (615584)
Cancer Research UK (C14303/A17197)
Wellcome Trust (107609/Z/15/Z)
Cancer Research UK (unknown)
Cancer Research UK (20412)
Wellcome Trust (202878/Z/16/Z)
Funded by the European Research Council (F.C., T.F.R., D.T.O., S.A.T., and M.J.T.S.), EMBO Young Investigators Programme (D.T.O.), Cancer Research UK (H.-C.C., M.d.l.R., D.T.O., and J.C.M.), Janet Thornton Fellowship (WT098051 to C.P.M.-J.), Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (107609/Z/15/Z to M.d.l.R.), European Molecular Biology Laboratory (N.E., A.A.K., M.J.T.S., S.A.T., and J.C.M.), Medical Research Council Biostatistics Unit (MRC_MC_UP_0801/1 to C.A.V.), WTSI (C.P.M.-J., S.A.T., J.C.M., and D.T.O.), and Biotechnology and Biological Sciences Research Council–Collaborative Awards in Science and Engineering Studentship with Abcam plc (A.A.K.).