Multidimensional single-cell analysis of human peripheral blood reveals characteristic features of the immune system landscape in aging and frailty

Frailty is an intermediate status of human ageing process, associated with decompensated homeostasis and death. The immune phenotype of frailty and its underlying cellular and molecular processes remain poorly understood. Here we profiled 114,467 immune cells from cord blood, young adults, healthy and frail elderly using single-cell RNA and TCR V(D)J sequencing. An age-dependent accumulation of cell heterogeneity and transcriptome variability in defined immune cell types was observed. With the specific expression of gene sets, characteristic transcription factors were identified in given immune cell types of certain age group. Trajectory analysis revealed cells from non-frail and frail elderly often fall into distinct trajectories, despite similar chronological age. Numerous TCR clonotypes were shared among T cell subtypes in aged and frail samples, indicating differential pluripotency and resilience capability of aged T cells. Finally, a frailty-specific monocyte subset was identified with exclusively high expression of lncRNAs NEAT1 and MALAT1. Our results discover human frailty-specific immune cell characteristics based on the comprehensive dimensions in immune landscape of ageing and frailty. Three cord blood samples, PBMC samples from 3 healthy young, 6 healthy old and 5 frail donors were used for single-cell RNA, TCR and cell surface protein (CCR7, CD45RA, CD4 and CD8) antibody barcoded sequencing to create a single-cell transcriptome and TCR atlas from newborns to frailty.