To determine how an increased MCs population and decreased TCs population at the onset of SARS-CoV-2 infection contribute to faster disease progression in the elderly at the cellular and molecular levels, we used scRNA-seq to investigate the association between aging and COVID-19. Specifically, we analyzed DEGs to explore whether differentially expressed SARS-CoV-2-related genes in aged patients could explain the impact that aging had on the susceptibility and recovery of COVID-19 patients in cohort-3 (Figs. S13A–C and S14A). ACE2 is not expressed by any blood immune cells, and recent studies have reported that CD147 (encoded by BSG), CD26 and ANPEP might be alternative cellular entry receptors for SARS-CoV-2, especially CD147, in TCs (Han et al., 2020; Qi et al., 2020; Ulrich and Pillat, 2020). Anti-CD147 antibody has been tested to treat COVID-19 patients with promising effects (Bian et al., 2020). We found that BSG expression in the AH group was increased in TCs, BCs and DCs, while ANPEP was only upregulated in MCs (Fig. 7A). Moreover, we found that aging increased the frequency of immune cells that expressed BSG and ANPEP (Fig. 7B). This result was validated using flow cytometry analysis, which showed increased CD147 expression in CD3+ TCs in the aged people compared with the young group (P = 0.0010, Fig. 7C). We further observed higher expression of the CD147-related genes NFATC1, ITGB1, and PPIB in CD4 Naive of the AH group (Fig. S14B–D). In addition, CD26 (encoded by DPP4), another potential SARS-CoV-2 receptor (Radzikowska et al., 2020), was only upregulated in CD4 Naive of the AH group (Fig. S14E). Altered expression of these molecules in circulating immune cells, especially in CD4 Naive, with age might contribute to increased susceptibility and severity of COVID-19 in the elderly. Figure 7 Aging and SARS-CoV-2 infection are characterized by similar hyper-inflammatory states. (A) Dot plot showing increased BSG and ANPEP expression in major immune cell populations in the AH group compared to YH group. P values are based on two-tailed Mann-Whitney-Wilcoxon tests between groups. (B) Expression levels of BSG and ANPEP in specific cell types in YH and AH groups. (C) Recapitulative graph of the MFI of CD147 expression in CD3+ T cells. MFI, mean fluorescence intensity. (D) Bar charts of the relative percentage of major immune cell populations derived from scRNA-seq data in YH, AH and ACR group (left), YCR and ACR group (right). (E) Venn diagram showing the integrated comparative analysis of upregulated DEGs in T cells between YH and AH group, YCR and YH group, ACR and AH group. The count shows the number of DEGs. (F) Venn diagram showing the integrated comparative analysis of upregulated DEGs in monocytes between AH and YH groups, YCR and YH groups, ACR and AH groups. The count shows the number of DEGs. (G) Volcano plot showing DEGs in T cells between YCR and ACR groups. P values were calculated using a paired, two-sided Wilcoxon test and FDR was corrected using the Benjamini-Hochberg procedure. (H) Volcano plot showing DEGs in monocytes between YCR and ACR groups. P values were calculated using a paired, two-sided Wilcoxon test and FDR was corrected using the Benjamini-Hochberg procedure. (I) Dot plot showing expression levels of the top 20 aging-induced and disease-associated genes in T cells per group in cohort-3. (J) Dot plot showing expression levels of the top 20 aging-induced and disease-associated genes in monocytes per group in cohort-3. (K) CT photography showing the different manifestation of evolution of Lung Ground-Glass Opacity in young and aged patients with COVID-19