Today's open access editorial discusses one quite specific consequence of the age-related disruption of energy metabolism in cells. Mitochondria, the power plants of the cell, falter with age throughout the body, for complex reasons still under exploration. The proximate causes involve too little production of molecular machinery needed for the correct operation of the electron transport chain, or mitochondrial dynamics, in the first case leading to inefficient production of ATP and raised levels of reactive oxygen species, and in the second case leading to failure of quality control mechanisms intended to remove worn and damaged mitochondria.
How these changes connect to the root causes of aging is yet to be established. It is possible that the recently discovered connection between characteristic age-related epigenetic changes, leading to changes in protein production, and cycles of double strand break repair will turn out to be important. Equally, most of the other deeper causes of aging are suspects. It is very challenging to pick through the complex web of interactions to reliably point blame at any one specific mechanism of aging.
Dysfunctional energy metabolism has many consequences, however. It is particularly implicated in age-related diseases of the brain, an energy-hungry tissue. The research materials here are interesting for the demonstration that myeloid cells of the innate immune system are an important part of the problem. A weight of evidence is growing over time for the importance of the immune system and inflammatory signaling in the development of neurodegenerative conditions. Connecting that to the known importance of energy metabolism in neurodegeneration is somewhat novel, however.
While cognitive decline is clearly underlined by synaptic and neuronal dysfunction, other players are emerging as critical elements in the equation of brain ageing. Inflammation seems to be one of those, with pro-inflammatory factors being associated with poor cognitive performance, pointing to immune cells as important regulators in this process. 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 of aged mice proves to be indeed 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. Surprisingly, restoring the PGE2 signaling in myeloid cells to a youthful state is enough to prevent age-dependent cognitive decline.
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. This study nicely illustrates the importance of the cellular metabolic state of myeloid cells: it highlights that not only the availability of glucose, but also its channeling into different pathways (glycolysis versus glycogen synthesis) contributes to maintaining proper myeloid function.