Today's commentary discusses recent research into age-related changes in myeloid cell lineages of the innate immune system. These cells are produced by hematopoietic stem cells in the bone marrow, and play important roles in immune function and tissue function throughout the body. With age, hematopoiesis becomes biased towards an ever greater production of myeloid cells at the expense of other immune cells, a problematic shift. As noted in this commentary, the changes also extend to the behavior of myeloid cells, and thus to the capabilities of the immune system.
The work here pinpoints one set of changes in myeloid cells outside the brain that nonetheless negatively affects cognitive function, most likely via increased inflammatory signaling. The chronic inflammation of aging is coming to be understood as an important contribution to neurodegeneration. Inflammation is a necessary and useful aspect of our biochemistry when it is present in the short term, in response to infection and injury, for example. When sustained over the long term, however, inflammation disrupts normal tissue function throughout the body - and inflammatory signaling originating outside the brain can pass the blood-brain barrier to alter the behavior of cells in the brain.
The immune system is drastically affected with ageing. While the adaptive immune response comprising B-cells and T-cells is diminished, the innate immune system (i.e., cells of the myeloid lineage) shows an increase in the pro-inflammatory state, also known as "inflammaging". This chronic low-inflammatory state is mainly driven by macrophages and pro-inflammatory cytokines.
Cellular metabolism has emerged as a key player in the regulation of immune function, starting already at the level of myeloid versus lymphoid lineage decision and greatly affecting cellular behaviour in the mature immune cells. Several recent studies have suggested that an altered cellular metabolism in aged macrophages might directly contribute to the pro-inflammatory signature. However, the detailed mechanisms initiating this increased inflammation with aging remain unclear.
In a recent publication, researchers have elucidated this cascade using an impressive set of in vitro and in vivo experiments in mice and in human myeloid cells. They found that aged myeloid cells have a decrease in cellular respiration and a decrease in glycolysis, suggesting that aged myeloid cells undergo a general bioenergetic failure. The proposed driving cause is the increased prostaglandin E2 (PGE2) signaling in the ageing myeloid compartment, mediated by the age-dependent upregulation of EP2, one of the four PGE2 receptors.
Conditional knockout of EP2, specifically in the myeloid cells (EP2 cKO) of aged mice proves to be an effective strategy at multiple levels. First, it rescues the expression of some of the immune factors upregulated with age, both in the plasma and in the hippocampus. Second, the loss of EP2 also reduces glycogen levels, normalizing the metabolic state and the associated mitochondrial defects observed in old macrophages. A similar effect is also mimicked by directly inhibiting GYS1. Third, strikingly, aged EP2 cKO mice appear to be completely protected from a decline in hippocampal-related memory functions with ageing.
Overall, this data supports an upstream role of peripheral myeloid cells in orchestrating the process of brain ageing, underscoring the important cross-talk between the immune and the central nervous systems.