The immune system ages in a variety of ways. It might be considered several overlapping systems that all interact closely with one another, while each component has its own distinct forms of dysfunction that arise in later life. Researchers here report on their investigation of aging in B cells, responsible for the generation of antibodies. They link aging to altered expression of genes related to IGF-1, an area of biochemistry long known to be influential in determining the pace of aging in mammals. Like most such well known aging-related regions of mammalian biochemistry, this touches on stress response and nutrient sensing, and is involved in the mechanisms by which calorie restriction extends life span.
Antibodies are generated in specialized cells called B cells. The pathway that generates these cells is highly complex, encompassing many precursor cell types. All of the early steps of this process occur in the bone marrow where dedicated precursor B cells are generated from hematopoietic stem cells. The aging process strongly impacts these early steps, with reduced numbers of precursor B cells and a decline in the developmental flow of these cells towards mature B cells that secrete antibodies. Importantly, this reduces the diversity of the antibody repertoire.
Since each B cell produces a different antibody, this is essentially a numbers game - the fewer B cell precursors you have, the less chance you have of producing a mature B cell with a good antibody match for any infection you may encounter. Precisely why the numbers of these precursors decline in the aged is not known. One theory is that this is linked to how genes are affected upon aging. Many genes code for proteins, the tools cells use for their function. Others code for regulatory molecules that control these proteins. The way genes are packaged and organized in the nucleus has a major impact on their expression, for example if they are switched on or off.
To test this theory, we decided to explore whether changes in the gene expression apparatus and genome organization in B cell precursors contribute to this decline. When we compared the expression of genes in B cell precursors from young and old mice, we found that aging affected only a relatively narrow set of genes. Significantly, several of these genes, including long, non-protein coding transcripts and small regulatory transcripts called microRNAs, participate in pathways that respond to nutritional status and link to growth and proliferation.
In particular, several key genes in the insulin-like growth factor (IGF) signaling pathway, a highly conserved regulatory pathway that is initiated by growth hormones in many cell types, were downregulated in the aged B cell precursor cells. We identified changes in genome organization that are linked to this downregulation. Our study suggests that relocation of genes between active and repressive nuclear environments might contribute to changes in gene expression upon aging. This is an unusual method of downregulation, since normally signalling pathways are modulated by fine tuning of cytoplasmic events, such as phosphorylation.