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

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JGM, Aged, Young Adult, Humans, Frailty, Frail Elderly, Aging, Immune System, Receptors, Antigen, T-Cell

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Nat Aging. 2022;2(4):348-64







This work was supported by funding from the National Key Research and Development Program of China (2021YFC2009404 to G.Z., 2018YFC2002003 to G.C., 2018YFC2002001 to J.G., 2018YFC2002002 to J.C., 2018YFC2002004 to N.P. and 2018YFC2002000 to Z.B.), the Natural Science Foundation of China (81971301 and 32050410285 to O.J.L., U1801285 to G.C., 81973221 to W.G. and 81971327 to E.F.F.), the Guangzhou Planned Project of Science and Technology (202002020039 to O.J.L., 202102010030 to G.Z. and 201904010111 to G.C.), the Initial Supporting Foundation of Jinan University (to O.J.L. and G.C.), the Milstein Medical Asian American Partnership (MMAAP) Foundation of the USA under the Irma and Paul Milstein Program for Senior Health (to G.C. and S.X.L.), the China Pharmaceutical University 2020 Innovation and Entrepreneurship Elite Cultivation Plan (to W.G.), Helse Sør-Øst (2017056 and 2020001 to E.F.F.) and the Research Council of Norway (262175 and 277813 to E.F.F.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.


Frailty is an intermediate status of the human aging process, associated with decompensated homeostasis and death. The immune phenotype of frailty and its underlying cellular and molecular processes remain poorly understood. We profiled 114,467 immune cells from cord blood, young adults and healthy and frail old adults using single-cell RNA and TCR sequencing. Here we show an age-dependent accumulation of transcriptome heterogeneity and variability in immune cells. Characteristic transcription factors were identified in given cell types of specific age groups. Trajectory analysis revealed cells from non-frail and frail old adults often fall into distinct paths. Numerous TCR clonotypes were shared among T-cell subtypes in old adults, indicating differential pluripotency and resilience capabilities of aged T cells. A frailty-specific monocyte subset was identified with exclusively high expression of long noncoding RNAs NEAT1 and MALAT1. Our study discovers human frailty-specific immune cell characteristics based on the comprehensive dimensions in the immune landscape of aging and frailty.