Restoring neutrophil clearance reverses aging hallmarks in mice

A previously unknown aging mechanism has been identified and reversed in mouse models: the accumulation of senescent neutrophils that tissue-resident macrophages progressively fail to clear with age. Researchers found that the PGE2-EP2 signal suppresses the phagocytic capacity of these long-lived macrophages, and that removing this brake—via TRM-specific EP2 deletion or pharmacologic antagonism—restores mitochondrial fitness and immune homeostasis across major organs. In aged mice, this intervention reversed cognitive decline, frailty, sarcopenia, cardiac dysfunction, and adiposity toward youthful states. Single-cell RNA sequencing revealed accumulation of senescent CXCR4+ neutrophils in liver and other organs, each exhibiting DNA damage response activation and anti-apoptosis programs that were efficiently cleared following EP2 deletion. Critically, human liver and heart datasets show this same pathway is upregulated in aged tissue-resident macrophages, positioning EP2 antagonism as a tractable therapeutic target for age-related functional decline.