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0This research identifies tissue-resident macrophages (TRMs) as essential regulators of systemic aging through their role in clearing senescent neutrophils. As organisms age, TRMs increasingly express the EP2 receptor, which triggers signaling pathways that disrupt mitochondrial health and impair the efferocytosis, or cellular disposal, of these short-lived immune cells. Consequently, uncleared neutrophils accumulate across major organs, undergoing degranulation and NETosis that cause chronic inflammation and tissue damage. Experimental evidence from mice shows that genetically deleting or pharmacologically inhibiting the EP2 receptor restores the ability of TRMs to stabilize and engulf these aging cells. This intervention successfully reversed multiple symptoms of decline, including cognitive loss, muscle wasting, and cardiac dysfunction, while shifting the plasma proteome back to a youthful state. Human data further confirms that EP2 upregulation and neutrophil accumulation are conserved features of aging, suggesting that targeting this clearance mechanism offers a viable therapeutic strategy for promoting healthspan.
References:
Tan Y J, Conley T E, Yao F, et al. Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging[J]. Science, 2026, 393(6808): eaea3075.
