Yingfeng Zheng, Xiuxing Liu, Wenqing Le, Lihui Xie, He Li, Wen Wen, and Si Wang have contributed equally.

ACKNOWLEDGMENTS
This work was supported by the National Key Research and Development Program of China (2017YFA0105804), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000), the National Key Research and Development Program of China (2018YFC2000100, 2017YFA0103304, 2017YFA0102802, 2018YFA0107203), the National Natural Science Foundation of China (81670897, 81625009, 91749202, 81861168034, 81921006, 31671429, 91949209, 91749123, 81671377, 81822018, 81870228, 81922027, 81701388, 81601233), the Program of the Beijing Municipal Science and Technology Commission (Z191100001519005), Beijing Natural Science Foundation (Z190019), Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), Advanced Innovation Center for Human Brain Protection (3500-1192012), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221), K.C. Wong Education Foundation (GJTD-2019-06, GJTD-2019-08), Youth Innovation Promotion Association of CAS (2016093), the State Key Laboratory of Membrane Biology and the State Key Laboratory of Stem Cell and Reproductive Biology.

ABBREVIATIONS
AA, aged healthy adults; ABC, age-associated B cell; ACO, aged COVID-19 onset patients; ACR, aged recovered COVID-19 patients; AH, aged healthy; ASC, antibody-secreting cell; BCs, B cells; CD4 Naive, naive CD4+ cells; CD4 Tcm, central memory CD4+ T cells; CD4 Tem, effector memory CD4+ T cells; CD4 Tex, exhausted CD4+ T cells; CD4 Treg, CD4+ regulatory T cells; CD8 CTL, cytotoxic CD8+ cells; CD8 Naive, naive CD8+ T cells; CD8 Tem, effector memory CD8+ T cells; CD8 Tex, exhausted CD8+ T cells; CyTOF, mass cytometry; DARs, differentially accessible regions; DCs, dendritic cells; DEGs, differentially expressed genes; DETs, differentially expressed transcription factors; GO, Gene Ontology; IFN-γ, interferon-gamma; Intermed, intermediate monocytes; MCs, monocytes; MEGAs, megakaryocytes; NK, natural killer; NK1, CD16− CD56bright NK; NK2, CD16+ CD56dim CD57− NK; NK3, the CD16+ CD56dim CD57+ late NK; NRF1, nuclear respiratory factor 1; PCA, principal component analysis; RBCs, red blood cells; RT-qPCR, quantitative reverse transcription polymerase chain reaction; scATAC-seq, single-cell assay for transposase-accessible chromatin sequencing; scRNA-seq, single-cell RNA sequencing; scTCR/BCR-seq, single-cell paired TCR/BCR sequencing; TCs, T cells; TFs, transcription factors; TNF, tumor necrosis factor; IL, interleukin; T-mito, mitotic T cells; t-SNE, t-distributed stochastic neighbor embedding; UMIs, unique molecular identifiers; YA, young healthy adults; YCO, young COVID-19 onset patients; YCR, young recovered COVID-19 patients; YH, young healthy.

DATA AVAILABILITY
The single-cell sequencing data is deposited in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG, https://bigd.big.ac.cn/gsa-human/), Chinese Academy of Sciences, with Project Accession No. PRJCA002865 and GSA Accession No. HSA000203. In cohort-3 scRNA seq, YCR and ACR data were obtained from the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG, http://gsa.big.ac.cn), Chinese Academy of Sciences, with Project Accession No. PRJCA002413 and GSA Accession No. CRA002497.

COMPLIANCE WITH ETHICS GUIDELINES
Yingfeng Zheng, Xiuxing Liu, Wenqing Le, Lihui Xie, He Li, Wen Wen, Si Wang, Shuai Ma, Zhaohao Huang, Jinguo Ye, Wen Shi, Yanxia Ye, Zunpeng Liu, Moshi Song, Weiqi Zhang, Juan Carlos Izpisua Belmonte, Chuanle Xiao, Jing Qu, Hongyang Wang, Guang-Hui Liu, and Wenru Su declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.