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- organ aging
(2 posts to January 2024).
The latest here:
Macrophage Receptor Blockade Reverses Multi-Organ Aging
Summary: Researchers unmasked a profound breakdown in the body’s internal garbage clearance system. As we age, tissue-resident macrophages lose their ability to engulf and dispose of expiring white blood cells, specifically short-lived neutrophils. Left un-cleared, these old cells transform into highly toxic, zombie-like “organ aging (2) neutrophils” that damage healthy tissues.
By blocking a single pro-inflammatory receptor known as EP2 exclusively on these long-lived macrophages, the team successfully revived their youthful cellular cleanup capabilities. This targeted intervention halted chronic inflammation and preserved the functional youthfulness of multiple vital organs throughout the body.
Key Facts
- The Neutrophil Garbage Crisis: The body produces roughly 100 billion neutrophils daily as frontline immune responders. Because their active lifespans rarely exceed 12 to 24 hours, long-lived tissue-resident macrophages are tasked with continuously clearing these defunct cells. With advanced age, an unrelenting surge of the pro-inflammatory hormone prostaglandin E2 (PGE2) binds to heavily concentrated EP2 receptors on macrophages, shutting down their cellular engulfing (phagocytosis) mechanism.
- The Rise of Zombie Neutrophils: Starved of proper macrophage clearance, expiring neutrophils undergo a swift transition into an intensely toxic, senescent state. These zombie cells accumulate within the liver, spleen, bone marrow, and other major organs, where they damage surrounding tissues by leaking destructive chemicals and propagating systemic inflammation.
- Widespread Multi-Organ Rejuvenation: Disabling or pharmacologically blocking the EP2 receptor exclusively on tissue-resident macrophages triggered sweeping systemic preservation in aged mice. Rejuvenation and a stark reduction in inflammation metrics were confirmed across a vast network of organs:
- Neurological Preservation: Deeply reduced hippocampal inflammation, preventing age-related memory loss and maintaining baseline spatial navigation and cognitive processing speeds.
- Metabolic Recovery: Drastically lowered visceral fat accumulation, preserved youthful skeletal muscle mass, and normalized 59 out of 71 age-altered blood proteins, primarily driven by restored liver homeostasis.
- Somatic Vitality: Aged mice treated with an experimental EP2 inhibitor looked leaner and exhibited physical speed, balance, and forelimb grip strength matching their youthful counter-cohorts.
- Human Translation Confirmed: Transitioning from mice to humans, the Stanford team analyzed comprehensive human hepatic databases. The dataset confirmed that older and diseased human livers exhibit the identical pathological cascade seen in the animal models: a dramatic neutrophil buildup, widespread cellular senescence, and heightened macrophage EP2 receptor activity.
- The Precision Medicine Alternative: Dr. Katrin Andreasson emphasizes that while current everyday painkillers (like aspirin or NSAIDs) reduce inflammation by blocking PGE2 production upstream, they are too clumsy, shutting down multiple beneficial prostaglandins and companion receptors. Developing a safe, highly selective drug that targets the EP2 receptor directly, without interfering with broader hormone systems, represents an outstandingly high-priority therapeutic path to extend human health spans.
- Source: Stanford
We may age at different rates, but none of us escapes aging. A study in mice and in human cells by Stanford Medicine researchers pins much of the blame on a particular type of immune cell’s increased 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.
“We’ve been trying to figure out why we age,” Andreasson said. “Now we know at least one big reason for it.”
The study’s findings are described in a paper to be published online July 16 in Science. Andreasson is the senior author, and the lead author is Jessy Tan, PhD, an instructor in neurology.
This discovery clarifies systemic inflammation’s outsized contribution to aging and the debilities that accompany it. And it suggests a pharmaceutical approach that could restrain our organs’ ineluctable march to senescence, extending our overall health spans.
A tale of two cell types
The most abundant white blood cells in our immune system are neutrophils, our bodies’ main first responders. Born in the bone marrow, new neutrophils hop into the bloodstream, where they circulate and, if they come across a bacterial, viral or fungal pathogen, go all medieval on it: They squirt out poison and perform a hara-kiri horror act, spilling their guts out and unloading long, stringy macromolecules that form weblike nets and trap the pathogen.
Perhaps unsurprisingly, neutrophils are extremely short-lived: They’re lucky to survive 24 hours (12 hours is more typical). Some 90% of circulating neutrophils end up in the liver, spleen and bone marrow, awaiting execution and riddance by another batch of immune cells.
This neutrophil clearance is critical. In aged animals, the vast bulk of neutrophils that never see combat undergo a fast transition to senescence, a zombie-like state in which they injure, age and inflame neighboring cells by vomiting toxic chemicals and otherwise behaving like an addled rock star punching holes in a hotel room wall.
The older we get, the more our neutrophil counts rise, with senescent neutrophils constituting an ever higher percentage.
“Senescent neutrophils are killing our tissues,” Andreasson said. “Clearance of these cells is essential for preventing chronic inflammation.”
That’s a job for another type of immune cell called a macrophage. These cells are by turns soldiers, builders, medics and garbage collectors. They comb the tissues for pathogens, chew them up, spurt signaling substances that summon other cells to lend a hand, and pump out growth factors that help repair damaged tissue.
First and foremost, Andreasson said, “They’re the body’s garbage collection crew. A lot of that garbage is defunct cells.” And a lot of those cells are neutrophils — to the tune of 100 billion a day.
Macrophages come in several subtypes. Tissue-resident macrophages are long-lived and ubiquitous. They take up residence in each of the body’s organs during fetal development and remain for their lifetimes in whatever organ they’ve inhabited, adapting their roles to fit that organ.
One of tissue-resident macrophages’ prime responsibilities is to swallow senescent cells. Especially important targets for this operation, the study showed, are some 100 billion neutrophils, produced daily, which start showing signs of senescence within 8 to 12 hours after entering the bloodstream. (Neutrophils that haven’t arrived at senescence yet but have lived long enough and seen enough to put out “kill me now” flags of surrender on their cell surfaces are fair game.)
But tissue-resident macrophages also grow old and tired and dyspeptic. As Andreasson and associates showed in a 2021 Nature paper, over the advancing years these long-lived cells become ever more prone to succumb to aging-associated inflammation and to propagate it.
A distress signal
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.
It’s a one-two punch: PGE2’s pro-inflammatory influence increases with age. The resulting unrelenting inflammatory PGE2 stimulation on tissue-resident macrophages, the new study showed, downshifts these voracious cells’ ability to wolf down neutrophils. Senescent neutrophils then accumulate in tissues and blood.
Andreasson and her colleagues have previously shown that with aging, tissue-resident macrophages undergo a slow decay in their energy metabolism. “Once that starts, there’s a steady decline in a macrophage’s performance,” she said.
In the new study, she continued, “We’ve shown that when tissue-resident macrophages don’t have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn’t happen.”
Block one receptor, rejuvenate many organs
Andreasson’s lab has 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.
For their experiments, the Stanford Medicine researchers studied younger normal mice (age 6 to 8 months) corresponding to late adolescence or early adulthood in humans; older normal mice (23 to 25 months), whose human counterparts would be in their 60s or 70s; and otherwise virtually identical 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,” Andreasson said. “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.
Seeking drugs to target EP2
There are, today, no approved drugs that selectively shut down EP2 activity, although there are several that target PGE2. Non-steroidal anti-inflammatory painkillers work by blocking PGE2 production, Andreasson said. (That’s how aspirin and similar drugs reduce pain, fever, swelling and redness, the “four horsemen” of inflammation.) But to greater or lesser degrees they all block other vital prostaglandins. Even PGE2 has beneficial properties when it binds to receptors other than EP2, rather than the detrimental inflammatory one examined in this study.
The investigators treated otherwise normal 22-month-old mice for two months with an EP2-inhibiting experimental drug.
This drug reduced total and senescent neutrophil counts in old mice toward youthful levels. In culture dishes, old age diminished — but the EP2-blocking drug likewise significantly restored — the mice’s tissue-resident macrophages’ ability to engulf and digest burnt-out neutrophils.
Finally, the team turned to a large database characterizing goings-on in all cell types in young, old and diseased human livers. This database revealed the same age-related neutrophil buildup, increased neutrophil senescence, tissue-resident-macrophage decline and heightened EP2 activity in older — and even more so, diseased — livers that the Stanford Medicine researchers had seen in mice. It was a first-time observation in human cells, according to Andreasson.
Targeting neutrophil clearance may yield big therapeutic benefits, she said: “We need to develop a safe drug” that incapacitates EP2 without disrupting upstream events such as PGE2 production.
A researcher from the University of Munster in Germany contributed to the work.
Funding: The study was funded by the National Institutes of Health (grants 1RF1AG080742, 1RF1AG070839 and P30AG066515), the American Heart Association, the Phil and Penny Knight Initiative for Brain Resilience (at the Wu Tsai Neurosciences Institute), Stanford University, the Arc Institute, and the Chan-Zuckerberg Biohub. The research was conducted in part at the Neurosciences Preclinical Imaging Community Laboratory at the Wu Tsai Neurosciences Institute.
Key Questions Answered:
A: Think of neutrophils as the kamikaze first-responders of the immune system. When you are young and get an infection, they swarm the site, unleash toxic chemicals to melt away pathogens, and deliberately burst open to form weblike nets that trap invaders. Because they are so intensely destructive, they are designed to die within 12 to 24 hours, at which point the body’s macrophage cleanup crews instantly sweep them away. However, as we age, the cleanup crew goes on strike. Left floating in our organs past their expiration date, these un-cleared neutrophils transform into hyper-toxic “zombie cells.” They wander through healthy tissues, punching holes in cell walls, vomiting inflammatory chemicals, and accelerating the physical aging of everything around them.
A: While everyday painkillers like aspirin or ibuprofen do reduce inflammation by shutting down the production of the prostaglandin PGE2, they act like biological sledgehammers rather than precision tools. PGE2 is a complex hormone that does many different jobs depending on which receptor it latches onto. When it hits the EP2 receptor on macrophages, it causes damage and shuts down clearance; however, when it binds to other receptors, it can actually support healing, protect the stomach lining, and assist blood vessel health. Blanket NSAIDs shut down the entire system, causing long-term side effects like ulcers or kidney stress. The Stanford team’s ultimate goal is to develop a hyper-targeted drug that leaves the helpful pathways completely alone, acting like a shield that plugs up only the problematic EP2 receptor.
A: For decades, the medical community viewed the aging of different organs—like cognitive decline in the brain, fatty buildup in the liver, and frailty in our muscles, as separate, distinct illnesses that required completely different treatments. This study completely upends that reductionist model. By demonstrating that deleting a single receptor on one type of immune cell simultaneously preserved the youthful function of the brain, heart, liver, muscles, colon, and kidneys, Stanford has exposed a universal master key to aging. It proves that we do not necessarily have to treat every organ disease individually; by simply fixing the body’s natural cellular garbage disposal system, we can halt systemic inflammation at its root, unlocking a future where overall human health spans can be extended in unison.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this aging research news
Author: Bruce Goldman
Source: Stanford
Contact: Bruce Goldman – Stanford
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging” by Abel Bermudez, Damilola E. Akinyemi, Fernando J. García-Marqués, Fuwen Yao, Jieun Kim, Julia A. Belk, Katrin I. Andreasson, Oliver Soehnlein, Qian Wang, Sharon J. Pitteri, Travis E. Conley, Van Vuong Dinh, Yuting Jessy Tan. Science
DOI:10.1126/science.aea3075
