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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

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

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.

Description

Keywords

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

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

355

Publisher

American Association for the Advancement of Science
Sponsorship
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)
Cancer Research UK (17043)
Cancer Research UK (22231)
Cancer Research UK (22257)
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.).