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Single-Cell Analysis Yields Immune Cell Atlas of Aging, Uncovers Frailty-Specific Immune Monocyte

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NEW YORK — Researchers have uncovered a new frailty-specific immune cell through a single-cell omics analysis.

Frailty, a state marked by reduced strength and increased vulnerability to disease, arises as people age but can develop at different ages among different individuals. Frailty also has a particular impact on the immune system, leading to deterioration.

By analyzing immune cell samples from cord blood, young adults, and healthy and frail older adults, researchers from Jinan University in China examined how immune cells differ at various life stages. Overall, the transcriptomes of immune cells became more heterogenous and variable with age, though the trajectory of immune cells from frail and non-frail older adults differ. As they reported in Nature Aging on Monday, the researchers additionally uncovered a monocyte specific to frail individuals that could contribute to their condition.

"The use of a functional classification of human aging, such as healthy aging versus frailty, might be a better categorical way to narrow down the variation, and distinguish the phenotypes and mechanisms between healthy and unhealthy aging," senior author Guobing Chen from Jinan and colleagues wrote.

The researchers analyzed mononuclear cells from cord blood, young adults about 30 years of age, healthy older adults about 86 years old, and frail older adults about 88 years old. Frailty was determined based on the Frailty Index scores.

The researchers generated single-cell RNA sequencing data for 114,467 mononuclear cells, which they clustered into 17 groups. These included — based on marker genes and the expression of cell surface proteins and TCRs — different types of T cells, B cells, natural killer cells, and myeloid dendritic cells. The portion of certain cell types varied by age, as core blood samples harbored few memory T cells, for instance.

As T cells made up more than half the cells in their analysis, the researchers re-clustered them to identify six groups of T cells. With age, the portion of these cells shifted. Cord blood contained largely naïve T cells, the portion of which then declined with age to about 25 percent. At the same time, the frail group had a higher proportion of CD4+ central memory T cells, while the healthy older adult group had more CD8+ central memory T cells and more T regulatory cells.

The researchers additionally examined the trajectories of immune cell types with aging. Memory T cells, for instance, began along one path that then split in three. Cord blood CD4+ central memory T cells concentrated on the early pre-split path, while about 60 percent of such cells from young donors fell along the first of the split paths and a quarter along a second path after the split.

But CD4+ central memory T cells from older healthy and frail individuals followed a different pattern. Most cells from healthy older individuals clustered along the early path or along the first post-split path, while cells from frail individuals fell along the second and third post-split paths. The CD4+ central memory T cells from frail individuals further had upregulated genes associated with the MHC II complex and T cell inhibition, which the researchers noted could indicate senescence and repression.

When the researchers conducted another round of clustering analysis, this time of monocytes, they uncovered a new cluster of monocytes specific to the frail individuals. These cells had increased expression of NEAT1, MALAT1, and a number of genes linked to inflammatory response and aging, and had decreased expression of genes involved in exocytosis, myeloid cell activation, and apoptosis. NEAT1, in particular, is associated with an inflammatory response and cell senescence.

"These findings potentially imply these frailty-specific monocytes were related to the deterioration of the immune status and unhealthy condition of frail patients," the researchers wrote.