Given the link between cellular metabolism and myeloid cell function 17, we tested whether PGE 2 signalling affected macrophage bioenergetics. We identified a significant increase in PGE 2 synthesis in human monocyte-derived macrophages (MDMs) from individuals of over 65 years of age, compared to those from younger individuals (below 35 years of age) ( Fig. We hypothesized that increases in PGE 2 might underlie the development of age-associated maladaptive inflammation and cognitive decline. Levels of PGE 2 increase in ageing and in neurodegenerative disease 18– 20. 1a) and a major modulator of inflammation 11. The lipid messenger PGE 2 is a downstream product of the cyclooxygenase 2 (COX-2) pathway ( Extended Data Fig. In line with this, recent studies indicate that ageing macrophages show marked decreases in glycolysis and mitochondrial oxidative phosphorylation that cause immune dysfunction 17.
To maintain homeostasis, immune cells require robust glycolytic and mitochondrial metabolism to meet the demand for energy and biosynthetic precursors. The underlying mechanisms that are responsible for the development of maladaptive myeloid phenotypes in ageing are not well understood however, previous work suggests that cellular energy metabolism has an important role in regulating the activation state and function of the immune system 12– 16. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In ageing macrophages and microglia, PGE 2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E 2 (PGE 2), a major modulator of inflammation 11. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Systemically, circulating pro-inflammatory factors can promote cognitive decline 7, 8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration 9, 10. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease 4– 6. Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty 1– 3.