Abstract
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
Highlights
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging
The total number of recovered cells was 61,202 comprising 41,208 cells for supercentenarians and 19,994 cells for controls, which is in the normal range of median gene and unique molecular identifier (UMI) counts per cell reported in the 10XQC database (Fig. 1B and SI Appendix, Fig. S1B)
We identified the major cell types comprising peripheral blood mononuclear cells (PBMCs), including: T cells (TC1 and TC2 clusters) characterized by CD3 and T cell receptor (TRAC) expression; B cells (BC cluster) characterized by MS4A1 (CD20) and CD19 expression; natural killer cells (NK cluster) characterized by KLRF1 expression; 2 subsets of monocytes (M14 and M16 clusters) characterized by CD14 and FCGR3A (CD16) expression, respectively; and erythrocytes (EC cluster) characterized by HBA1 expression (Fig. 1D and SI Appendix, Fig. S1E)
Summary
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Numerous studies have examined age-related alterations in whole blood and peripheral blood mononuclear cells (PBMCs), derived from healthy donors in a wide range of age groups. Fluorescence activated cell sorting (FACS) and transcriptome sequencing technologies, which are extensively used to profile circulating immune cells, have revealed that the population makeup and expression levels of peripheral lymphocytes change dynamically with age. Naïve T cell numbers tend to decrease according to age, whereas antigen-experienced memory T cell numbers increase with concomitant loss of costimulation factors CD27 and CD28 [17] This tendency is more pronounced for CD8 T cells in cytomegalovirus seropositive donors [18]. Elderly hematopoietic stem cells in bone marrow exhibit a myeloid-biased differentiation potential [12, 13], which causes changes in the cell population of peripheral blood
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