Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity

Abstract

Age-related changes in immune cell composition and functionality are associated with multimorbidity and mortality. However, many centenarians delay the onset of aging-related disease suggesting the presence of elite immunity that remains highly functional at extreme old age. To identify immune-specific patterns of aging and extreme human longevity, we analyzed novel single cell profiles from the peripheral blood mononuclear cells (PBMCs) of 7 centenarians (mean age 106) and publicly available single cell RNA-sequencing (scRNA-seq) datasets that included an additional 7 centenarians as well as 52 people at younger ages (20-89 years). The analysis confirmed known shifts in the ratio of lymphocytes to myeloid cells, and noncytotoxic to cytotoxic cell distributions with aging, but also identified significant shifts from CD4+ T cell to B cell populations in centenarians suggesting a history of exposure to natural and environmental immunogens. Our transcriptional analysis identified cell type signatures specific to exceptional longevity that included genes with age-related changes (e.g., increased expression of STK17A, a gene known to be involved in DNA damage response) as well as genes expressed uniquely in centenarians PBMCs (e.g., S100A4, part of the S100 protein family studied in age-related disease and connected to longevity and metabolic regulation). Collectively, these data suggest that centenarians harbor unique, highly functional immune systems that have successfully adapted to a history of insults allowing for the achievement of exceptional longevity.

Enhanced insulin‐regulated phagocytic activities support extreme health span and longevity in multiple populations

“…(b-c) Genes involved in oxidative phosphorylation were enriched in both CD14 and CD16 monocytes harvested from Japanese supercentenarians as compared to the corresponding controls. of the declining adaptive immune system, in agreement with many previous finding (Karagiannis et al, 2022;Moskalev et al, 2020); so as an unexpected increment of the innate monocytes population, accompanied with activated phagocytic and lysosomal functions. RNA synthesized in the lymphocytes are degraded without even participating in any defense-related protein synthesizing purposes (Cooper, 1970).…”

Bayesian Differential Analysis of Cell Type Proportions

“…We demonstrate this model and approach using cell type distribution data of 66 subjects from single cell transcriptomics datasets of aging and longevity. The data is described in Karagiannis et al (Karagiannis and others 2022).…”

“…As an example, we used this approach to characterize the distribution of PBMCs at different ages. We used single cell transcriptomics data of PBMCs from 66 male and female subjects across four age groups with ages 20-119 years to identify 13 immune cell types based on specific gene signatures (Karagiannis and others 2022). We applied the proposed Bayesian multinomial regression model to the distributions of the 13 immune cell types and used 1,000 MCMC iterations with 500 iterations for burn-in to estimate cell type proportions and 95 percent credible intervals for males and female subjects for each age group across all immune cell types.…”

“…Comparing the estimated cell type proportions to the relative proportions across subjects, we found similar results across cell types. Full results are described in Karagiannis et al (Karagiannis and others 2022).…”

“…However, there are situations where no such reference cell type can be determined. For example, in our ongoing study of the distribution of peripheral blood mononuclear cells (PBMCs) with age, we could not identify a cell type with stable proportion in various age groups (Karagiannis and others 2022). To circumvent this problem, we present an alternative Bayesian multinomial regression analysis of cell type composition.…”