INTRODUCTION
The world population is undergoing a rapid expansion of older adults, and thus, exploring how to stay healthy with age has become an urgent global focus. Aging leads to numerous physiological changes, including the deterioration of the immune system, rendering the elderly more susceptible to infections, such as the COVID-19 pandemic, and poor responses to vaccines (Ciabattini et al., 2018; Alpert et al., 2019; Onder et al., 2020; Verity et al., 2020). Changes observed during aging are often reflected as alterations in the composition and functional declines of diverse immune cells. For T cells (TCs), the high frequency of naive cells in young humans progressively decreases along with the accumulation of highly differentiated memory cells (Hakim and Gress, 2007), whereas nonclassical monocytes (MCs) with high levels of plasma tumor necrosis factor (TNF)-α and interleukin (IL)-8 accumulate with age (Ong et al., 2018). In addition, senescence of the immune system in the elderly has been termed “inflammaging”, which refers to increased levels of tissue and circulating proinflammatory cytokines in the absence of an immunological threat (Panda et al., 2009; Franceschi et al., 2018). Overall, aging is associated with changes in the structure of diverse immune compartments, where accumulating dysfunctional subsets contribute to immune failure.
Seminal studies have provided insights into the compositions and functional alterations occurring during aging, primarily based on previously described markers detected in pooled heterogeneous cell populations. The recent development of unbiased high-throughput single-cell technologies with high accuracy and specificity has begun to change immunological studies, as researchers worldwide are ushering in the new field of systems immunology. By using single-cell sequencing, recent studies have reported that cell-to-cell transcriptional variability increases with age in CD4+ TCs (Bahar et al., 2006; Martinez-Jimenez et al., 2017) and in leukocytes from old mouse lungs (Angelidis et al., 2019). Aging also increases the variations in chromatin modifications of human immune cells (Cheung et al., 2018). Very recently, many immunological phenotypes, such as intratissue accumulation of proinflammatory cells, have been reported in aging rodent and primate models (Messaoudi et al., 2006; Watson et al., 2017; Hammond et al., 2019; Ma et al., 2020). However, a comprehensive aging cell atlas of human peripheral blood that systematically connects all the blood lineages and cell subtypes has not yet been constructed.
Here, we applied single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to comprehensively characterize the properties of peripheral blood mononuclear cells (PBMCs) in young and old adults. We also enrolled young and aged COVID-19 patients in the incipient stage and recovery stage to explore how age influenced the capacity for recovery and prognosis of COVID-19 infection and to better understand the influence of immune dysregulation in aging and infection. Our data revealed that aging promotes the polarization of TCs from naive and memory to effector, exhausted and regulatory subtypes and increases the numbers of late natural killer cells (NKs), age-associated B cells (BCs), inflammatory MCs, and dysfunctional dendritic cells (DCs). With single-cell paired T/B cell receptor sequencing (scTCR/BCR-seq), we uncovered decreased diversity and increased clonality of effector, cytotoxic and exhausted CD8+ TC subsets in TCs and age-associated B subsets in BCs with age. Notably, aging increased the expression of inflammation-related genes, senescence-related genes, and coronavirus susceptibility genes in specific cell subtypes. Most impressively, COVID-19 caused similar immune cell landscape changes to that of aging and further increased aging-induced immune cell polarization and upregulation of inflammatory genes. Increased SARS-CoV-2 susceptibility gene expression and inflammatory MCs and decreased TCs aggravate inflammatory storms and lymphopenia (Mehta et al., 2020; Merad and Martin, 2020; Zhou et al., 2020) and likely underlie the high susceptibility and mortality of old patients. Overall, this work expands our knowledge of aging via single-cell transcriptomic, proteomic and chromatin accessibility immune cell profiling and highlights critical nodes between the dysregulated immune system and infections that may serve to modulate the process of inflammaging.