Immune Cell Epigenetics Become More Disarrayed with Age

In this study, researchers note that at least some subsets of immune cells in older animals exhibit greater variability in gene expression (and thus behavior) than is the case in younger animals. At this point in the development of the work we can only speculate as to how this fits in to what is known of aging in general and aging in the immune system specifically. Is it a result of cells reacting to locally different levels of damage, or to secondary changes in cell signaling that vary more widely in older individuals because of molecular damage? Are the immune cells themselves relatively damaged, or does the presence of some damaged immune cells produce problems in communication and coordination across the whole population? These and other questions lack definitive answers at this time.

Researchers have shown that immune cells in older tissues lack coordination and exhibit much more variability in gene expression compared with their younger counterparts. We've all witnessed the progressive decline of function that comes with ageing, but what exactly causes this decline - and why does it happen at different rates for different parts of the body? To find answers, scientists need to unpick all of the mechanisms of ageing at the molecular level, for every tissue. This study focused on immune tissue: specifically, CD4+ T cells.

The immune system is like a symphony orchestra, with many different types and subtypes of cells working together to fight infections. But as the immune system ages, its response to infection weakens for reasons that are not yet clear. One long-standing debate amongst scientists concerns two central hypotheses: either the functional degradation is caused by a loss of cellular performance, or it is down to a loss of coordination among cells. To resolve the debate, scientists have studied many different cell types, analysing 'average' gene expression profiles. This study employed high-resolution single-cell sequencing technology to create new insights into how cell-to-cell variability is linked with ageing. The researchers sequenced the RNA of naïve and memory CD4+ T cells in young and old mice, in both stimulated and unstimulated states. Their findings clearly showed that loss of coordination is a key component of the impaired immune performance caused by T cell ageing.

"Imagine the immune system as a 'cell army', ready to protect the body from infection. Our research revealed that this army is well coordinated in young animals, with all the cells working together and operating like a Greek phalanx to block the infection. This tight coordination makes the immune system stronger, and allows it to fight infection more effectively. We show that as the animal gets older, cell coordination breaks down. Although individual cells might still be strong, the lack of coordination between them makes their collective effectiveness lower." Previous studies have shown that in young animals, immunological activation results in tightly regulated gene expression. This study further reveals that activation results in a decrease in cell-to-cell variability. Ageing increased the heterogeneity of gene expression in populations of two mice species, as well as in different types of immune cells. This suggests that increased cell-to-cell transcriptional variability may be a hallmark of ageing across most mammalian tissues.



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