Fight Aging!

Senescent cells accumulate with age in tissues throughout the body. These cells cease replication and secrete a potent mix of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained over the long term. Cells become senescent throughout life in response to various circumstances, but in youth are efficiently destroyed by the immune system. With old age, the immune system falters in this task for reasons that are still being explored in detail. While the increased damage and disarray found in aged cells and tissues likely accelerates the pace at which cells become senescent, present evidence suggests that immune dysfunction in the matter of senescent cell clearance is the dominant factor in the increased presence of lingering senescent cells in later life.

Various approaches to selectively removing senescent cells from aged tissues have been demonstrated in animal studies, such as the first generation of senolytic drugs (including the combination of dasatinib and quercetin) that sabotage mechanisms that senescent cells use to resist programmed cell death. A number of the biotech companies founded to develop senolytic drugs are focused instead on immunotherapies, ways to adjust the behavior of the immune system so that it can better target senescent cells for destruction. Today's scientific paper reports a novel basis for anti-senescence immunotherapy, based on removing an impediment to the ability of macrophages to destroy senescent neutrophils. Beyond the novel senolytic approach, the work is interesting for demonstrating that senescent neutrophils in and of themselves make up a sizable fraction of the entire problem of cellular senescence, at least in the liver and heart.

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear. Tissue-resident macrophages (TRMs), long-lived cells that comprise 60 to 90% of macrophages in major organs, maintain homeostasis through efferocytosis of apoptotic and senescent cells. Neutrophils, the most abundantly produced and shortest-lived leukocytes (more than 100 billion generated daily in humans), require continuous TRM clearance; uncleared aged neutrophils release proteases and extracellular traps that damage tissues and propagate aging. TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging. Whether impaired TRM efferocytosis drives the accumulation of senescent neutrophils that promote organ aging and whether inhibition of EP2 signaling can restore this process, remain unknown.

In aged mice, TRM-specific EP2 deletion restored mitochondrial fitness and immune homeostasis, and reversed cognitive decline, frailty, sarcopenia, adiposity, and cardiac dysfunction toward youthful states. Plasma proteomics identified the liver as a major source of age-associated immune changes. Single-cell RNA-seq of mouse liver and multiorgan flow cytometry revealed accumulation of senescent CXCR4+ neutrophils across efferocytic organs in aging. These cells exhibited the senescence-associated secretory phenotype (SASP), DNA damage response activation, cell cycle inhibitor induction, NETosis, and anti-apoptosis programs, and were efficiently cleared following EP2 deletion.

Liver multiplex imaging localized paracrine stress to parenchymal cells neighboring senescent neutrophils. Ex vivo efferocytosis assays showed that aged TRMs were most impaired in clearing senescent neutrophils relative to apoptotic substrates, with both functions restored by EP2 deletion or pharmacologic antagonism. Mechanistically, EP2 signaling suppressed integrin-dependent stabilization of senescent neutrophils on TRMs and downstream engulfment. Analyses of human liver and heart datasets revealed conserved EP2 up-regulation in aged TRMs, enrichment of senescent neutrophils, and reduced TRM-neutrophil interactions.

This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration. With age, neutrophils acquire senescence-associated features, and their accumulation drives tissue injury through two converging mechanisms: intrinsic degranulation and NETosis, and extrinsic paracrine stress on neighboring parenchymal cells. Pharmacological inhibition of EP2 restores TRM efferocytic capacity and promotes clearance of senescent neutrophils, positioning EP2 antagonism as a tractable therapeutic strategy for age-related organ and functional decline.