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"Two immune cell types’ contact plays a major role in aging. Blocking a hormone’s influence on one of those cell types halted mice’s age-associated decline in multiple organs."
"... A study in mice and human cells by Stanford Medicine researchers pins much of the blame on a particular type of immune cell's increasing inability, with advancing age, to gobble up another immune cell type. ...
So-called tissue-resident macrophages appear to be central coordinators of age-related organ decline. Blocking a single receptor on these cells preserved the youthfulness of multiple organs in mice including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone known to cause inflammation and pain in humans as well as mice.
In mice, selectively disabling this receptor exclusively on tissue-resident macrophages prevented chronic-inflammation-driven disorders of age including frailty, excessive fat accumulation and heart trouble; it also substantially slowed cognitive decline ...
Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE2, can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface.
Of the various subtypes of receptors for PGE2, one designated EP2 is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.
Infection, injury and toxic chemicals including the ones produced by our aging bodies increase PGE2 output. As the 2021 Nature paper showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages. ...
bioengineered a mouse in which, at a time of the scientists’ choosing, the gene that’s a recipe for EP2 gets deleted — but only in tissue-resident macrophages. The subsequent disappearance of EP2 from these cells, the new study proves, reinvigorated the neutrophil-devouring process that PGE2 undermines. ...
older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (their “teenage” years).
The scientists identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver.
“The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” ... “It’s the central organ determining the body’s metabolic rate.”
Smoldering senescent neutrophils, the study showed, accumulated in normal old mice’s livers, spleens and bone marrow — and, to a lesser extent, in all the many other bodily organs the researchers looked at.
But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.
EP2 deletion reduced inflammation in the blood, liver, colon, heart, kidney and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance and forelimb grip strength resembled that of young animals.
Reducing EP2 action in older mice also preserved their memory capabilities. They could thread their way through a maze or recall previously encountered objects almost as well as younger mice — and far better than similarly old mice in whose tissue-resident macrophages EP2 remained functional. ..."
From the abstract of the Perspective:
"Human aging is asynchronous. Cells, tissues, and organs deteriorate at different rates, an unevenness that may help explain the differential aging trajectories of people.
Elucidating both the overlapping and distinct biological pathways that contribute to cell-tissue-organ aging could guide strategies to promote health longevity. ...
Tan et al. (1) report that the oxylipin prostaglandin E2 (PGE2) undermines the capacity of tissue-resident macrophages (TRMs) from clearing out old, and hence damaging, neutrophils in aging organs.
n a mouse model, this housekeeping process can be restored if PGE2 action is blocked. The implication is that organ aging is not fixed but may be shaped by specific interventions that slow the decline."
From the editor's summary and abstract:
"Editor’s summary
Increased inflammation is associated with aging and is implicated in decreased function in aging tissues.
Tan et al. explored changes in older tissue-resident macrophages and investigated how these cells may contribute to aging phenotypes in mice ...
They found that signaling by the lipid messenger prostaglandin E2 was increased in these cells. In various mouse tissues, preventing an increase in tissue-resident macrophages helped to maintain mitochondrial function and limited other deleterious effects of aging. Tissue-resident macrophages help to reduce inflammation by removing apoptotic and damaged cells.
One consequence of inhibiting prostaglandin E2 signaling was restored clearance of senescent neutrophils. These results emphasize the possible roles of macrophages and neutrophil clearance in tissue disfunction during aging. ...
Structured Abstract
INTRODUCTION
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.
RATIONALE
We studied aged mice in which EP2 signaling on TRMs was selectively reduced, either genetically (TRM-specific EP2 deletion) or pharmacologically, to define how TRM dysfunction shapes organ-wide aging.
TRMs are long-lived gatekeepers of tissue homeostasis, and EP2 offers a tractable target because its activity increases in aged macrophages and suppresses their metabolic and phagocytic function.
Using complementary genetic and pharmacological approaches, we tested whether restoring TRM function reverses organ aging and identified which efferocytic substrate is most affected. The same design also defined the molecular step at which EP2 acts within TRMs and extended our findings to aged human tissues.
RESULTS
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.
CONCLUSION
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."
Breakdown of immune cells' interaction is key driver in aging, study finds
Tissue-resident macrophage (TRM) clearance of senescent neutrophils is restored by EP2 deletion or inhibition to limit organ aging.
