Abstract
Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies.
Highlights
Differences in immune function and responses contribute to health- and life-span disparities between sexes
Male and female samples for each assay were comparable in terms of frailty scores, BMI, and age except for young samples profiled with flow cytometry; young women were slightly older than men (~32.3 vs. ~28.35) (t-test p-value = 0.05) (Supplementary Table 1)
Annotation of PC1-related genes using immune modules[13] revealed genomic declines associated with the ‘T cell’ module and gains associated with ‘myeloid lineage’ and ‘inflammation’ (Fig. 1c), confirmed by enrichment analyses based on single-cell RNA-seq data (Supplementary Fig. 1c). These results suggest that aging is the main driver of variation in peripheral blood mononuclear cells (PBMCs) epigenomes/transcriptomes, where age-related variation is negatively associated with naive T cells and positively associated with myeloid lineage and inflammation, in agreement with the signatures of immunosenescence including impaired responsiveness of adaptive immunity and increases in low-grade and systemic inflammation with age, which together contribute to aging diseases[14]
Summary
Differences in immune function and responses contribute to health- and life-span disparities between sexes. We characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq, and flow cytometry These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. Recent studies revealed that chromatin accessibility of purified immune cells, especially CD8+ T cells, change significantly with aging, impacting the activity of important receptor molecules, signaling pathways, and transcription factors (TF)[4,5] Together, these changes likely contribute to aging-related immunodeficiency and to increased frequency of morbidity and mortality among older adults. Computational pipelines for functional enrichments, trajectory and breakpoint analyses revealed immune system aging signatures including longitudinal genomic trends These findings uncovered in which ways aging differentially affects the immune systems of men and women. These results are shared via a searchable R Shiny application (https://immune-aging.jax.org/)
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