Aging and the intricacies of the immune system

Why do our immune systems get worse as we age? New mouse model research published in Genome Biology explores the hypothesis that altered gene regulation in the precursors of specialized immune cells called B cells causes them to decline as we age. The study found aging to affect several genes that participate in pathways linked to growth and proliferation making this an important step forward in understanding aging and the immune system.

Thanks to improvements in healthcare, nutrition and lifestyle conditions, lifespan has doubled over the course of a couple of centuries. A baby girl born in 1841 could expect to live to 42: a baby girl born in 2016 can expect to live to 83. People are living longer and older people are healthier than they ever were.

Nevertheless, gains in healthspan have not kept pace with lifespan. An aging population  presents major economic, health and social challenges. To overcome these challenges we need to understand the aging process and use this knowledge to secure healthy aging and wellbeing in later life.

As we age, it becomes apparent that tissues age differently. For example, Patrick’s hair started to grey when he turned 40 (Anne’s is still fair, see our photos) and both of us were required to get reading glasses when we reached our 50s (recently!).

Aging impacts the immune system

In the immune system, the involution (shrinking) of the thymus, which occurs at puberty, might be considered as one of the first steps down the path of aging, preceding a general decline of the immune system much later in age. In fact, one might call age a form of acquired immune deficiency.

It is now well established that elderly people become more vulnerable to infection, such as pneumonia, and less responsive to immunization. This susceptibility is indicative of the loss of function of the adaptive branch of the immune system, which generates antibodies that are essential to fight many infections.

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 (blood generating) stem cells.

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.

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.

Aging and gene regulation

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. Due to the difficulty on obtaining human bone marrow under experimental conditions, we pursued these studies in the mouse immune system which is closely related to the human counterpart.

Several groups at the Babraham Institute contributed their expertise, including the labs of Peter Fraser, Mikhail Spivakov, Patrick Varga-Weisz, Sarah Elderkin and Anne Corcoran. This team effort generated the first integrative study examining how aging affects gene expression through genome regulation in B cell precursors in mouse bone marrow.

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.

Several key genes in the insulin-like growth factor (IGF) signaling pathway … were downregulated in the aged B cell precursor cells.

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.

Remarkably, several groundbreaking studies in the past have shown that deletion or mutation of components of the IGF pathway can extend lifespan in several model organisms, such as worms, flies and mice, and genetic studies have also seen some evidence for this in humans.

This may be for a variety of reasons including diminished susceptibility to external stress due to reduced metabolism or cellular proliferation. To our knowledge, the surviving B cells in aged mice are the first example of aging cells that ‘naturally’ downregulate this pathway.

While our findings constitute a step forward, there are many open questions. Future research should elucidate to what extent the changes we observe are intrinsic to the B cell precursors or depend on the altered environment these cells find themselves in, as the bone marrow changes in aging. Furthermore, we need to understand if the changes contribute to greater resilience of the cells or negatively affect their functions.

An exciting question for future research is whether these regulatory mechanisms affect other tissues and systems during aging.

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