Rejuvenation researchJan 25, 2021

Changing metabolism refreshes aged immune cells and restores thinking ability

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Inhibiting EP2 may improve age-associated cognitive impairment by restoring youthful metabolic functions.

Inflammaging is linked to cognitive decline and neurodegeneration as individuals age.
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with a lower incidence of Alzheimer's disease but has shown disappointing clinical trial outcomes.
Prostaglandin E2 (PGE2) activates receptors that reduce energy production processes like glycolysis and oxidative phosphorylation during aging.
Targeting EP2 with small molecule drugs shifts macrophages to an anti-inflammatory state and enhances metabolic processes.
Restoration of youthful mitochondrial structure and memory functions in the hippocampus occurs with EP2 inhibition.

Simplified

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.

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Changing metabolism refreshes aged immune cells and restores thinking ability

Abstract

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