Metabolic Reprogramming Rejuvenates Aged Myeloid Cells Restoring Cognition

Inflammaging is associated with aging-associated cognitive loss and neurodegeneration. Chronic nonsteroidal anti-inflammatory drug (NSAID) use has been reported to reduce the incidence of Alzheimer's disease (AD), presumably by inhibiting inflammation, although NSAIDs appear to not be good candidates for anti-AD therapeutics given disappointing clinical trial results. Prostaglandin E2 (PGE2) acts downstream of NSAID target COX-2, a cyclooxygenase, to activate several G-protein coupled receptors (GPCRs) including EP2, which is now reported to reduce glycolysis and oxidative phosphorylation during aging by increasing glycogen synthesis and polarizing myeloid cells toward the M1 proinflammatory phenotype. Inhibiting EP2 using small molecule drugs polarizes macrophages toward the anti-inflammatory phenotype, restores youthful metabolism and mitochondrial morphology as well as youthful hippocampus-based memory capability. EP2 may be a better target than COXs for the development of drugs that improve age-associated mild cognitive impairment and possibly even for the development of drugs to treat dementias.