Targeting acid ceramidase could improve healthy aging and longevity

 

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Ferroptosis (15 posts to July 2012)

Targeting acid ceramidase could improve healthy aging and longevity

Our population is aging. The United Nations reports that by 2050, the number of people over the age of 85 on our planet is set to triple. But a longer life span isn't the same as a longer healthspan (the number of years we spend healthy). Salk Institute scientists are working to change that through foundational research that explores the cellular mechanisms driving age-related dysfunction.

The latest efforts to understand cellular aging look at two processes prevalent in aged cells: 1) senescence, in which cells stop dividing but don't die, and 2) ferroptosis, in which cells lose their ability to regulate fats and eventually die. While studying human lung cells, the Salk team discovered that elevated levels of the enzyme acid ceramidase make senescent cells more susceptible to ferroptosis and can pass that vulnerability to neighboring cells.

Experimental drugs that target acid ceramidase have already been developed for other therapeutic purposes, demonstrating that acid ceramidase is targetable and lighting the way to future innovation that could extend healthspans.

The study published in Cell Death and Disease on July 10, 2026.

Senescent cells are linked to many age-related conditions, including arthritis, poor wound healing, and neurodegenerative diseases like Alzheimer's or Parkinson's. Our findings are a big milestone in the ongoing public health effort to support healthy aging, as we now have a novel target for developing new therapeutics that could be applied to a multitude of diseases and disorders."

Pam Maher, PhD, senior and co-corresponding author, research professor, Salk Institute

What are ferroptosis and senescence?

Maher is the person to ask about ferroptosis-she discovered the cellular pathway and named it ("oxytosis" originally) in 2001. Ferroptosis is an iron-dependent cell death pathway in which the accumulation of lipid peroxides becomes toxic to cells. Healthy cells keep lipid peroxides at steady levels with the help of glutathione, an antioxidant that can stave off ferroptosis.

Recent studies have reinforced links between ferroptosis and Alzheimer's and Parkinson's diseases, including another recent study from Maher's lab. In their recent Cell Death Discovery paper, Maher's lab discovered that chronic iron overexposure in neurons makes them less resilient over time and more vulnerable to neurodegeneration.

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This study is one of many to link ferroptosis to neurodegeneration, as targeting the pathway has become a promising therapeutic strategy for age-related diseases, alongside another growing area of interest: senescence.

Cellular senescence is a biological process in which cells don't completely die but also aren't quite alive. Often referred to as "zombie" cells, senescent cells are a hallmark of aging. Though sometimes they are harmless, other times they release harmful factors into surrounding tissues and can promote the development of diseases or disorders, including cancer.

Are ferroptosis and senescence connected during aging?

Since ferroptosis and senescence have been independently linked to age-related dysfunction, and both have become promising therapeutic targets for age-related diseases, the Salk team wondered whether there was any overlap in the two cellular processes.

To find an answer, the researchers cultured senescent human lung cells in the lab. Then, they induced ferroptosis in the senescent cells to find they were far more sensitive to the cell death pathway than young, healthy cells. The sensitivity began as senescent cells expressed progressively higher levels of an enzyme (a type of protein that can speed up chemical reactions inside cells) called acid ceramidase.

After discovering that excessive acid ceramidase drives cell sensitivity to ferroptosis, the researchers removed the enzyme from senescent and non-senescent cells to see whether its absence would make cells more resilient to induced ferroptosis. And it did. Removal of acid ceramidase from cells protected both young and old cells from ferroptosis.

"This is an entirely novel pathway that is independent of the mechanisms usually associated with ferroptosis-induced cell death, as it doesn't involve any changes in iron or glutathione levels but instead modulates the lipid metabolism," says first author David Soriano-Castell, PhD, a postdoctoral researcher in Maher's lab.

The Salk team also observed something else: Vulnerable senescent cells were able to pass their vulnerability on to neighboring cells. This helps explain why only a few senescent cells can turn into more, ultimately impacting a larger tissue, as time goes on.

"We have unraveled a new mechanistic connection between ferroptosis and senescence," explains Soriano-Castell. "This gives us a clear target that would eliminate two birds with one stone, eliminating senescent cells and keeping neighboring cells healthy for longer."

How does this advance healthy aging?

Unrelated to the Salk study, scientists have already developed drugs to target acid ceramidase for the treatment of other diseases in which this enzyme also plays a role. The Salk findings bring forward a new potential use case for these drugs, and the fact that they are already in development is a great proof-of-concept that drugs can, in fact, be designed to target the enzyme.

"This is only the beginning," says Soriano-Castell. "The next step is finding a more complete pathway and translating into animals and tissues, then clinical trials of our own, and so on. But what is important is that acid ceramidase is targetable, and other labs have already gotten that work started-later on, we can hopefully build on what they learn."

"The more we learn about ferroptosis," adds Maher, "the more possibilities there are for healthy aging innovations. This is an exciting time to be studying aging, resilience, and longevity, and I look forward to continuing to see how ferroptosis can be a useful target."

Source:

Salk Institute

Journal reference:

Soriano-Castell, D., et al. (2026). Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in WI-38 replicative senescent cells. Cell Death & Disease. DOI: 10.1038/s41419-026-09108-y. https://www.nature.com/articles/s41419-026-09108-y

Macrophage Receptor Blockade Reverses Multi-Organ Aging

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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.

Targeting the pro-inflammatory EP2 receptor on tissue-resident macrophages restores the clearing of senescent neutrophils, successfully reducing systemic inflammaging to preserve youthfulness across the brain, liver, heart, and skeletal muscles. Credit: Neuroscience News

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, said Katrin Andreasson, MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences.

“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:

Q: Why are neutrophils so helpful in youth but so incredibly destructive to our tissues as we get older?

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.

Q: If we already have anti-inflammatory drugs like aspirin that block this hormone pathway, why can’t we just use those to stop aging?

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.

Q: What makes this discovery a true paradigm shift for the future of longevity and preventative medicine?

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

Simple blood test could help predict progression of Parkinson disease

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Parkinson’s Disease May Have Link to Stroke March 2017

 

Simple blood test could help predict progression of Parkinson disease

MedicalXpress Breaking News-and-Events | February 11, 2020

In order to provide the best medical care for newly diagnosed Parkinson disease (PD) patients, a method of predicting their cognitive and motor progression, beyond using purely clinical parameters, would have major implications for their management. A novel study published in the Journal of Parkinson's Disease suggests that a blood test for inflammatory and cell senescence biomarkers may be a reliable predictor of cognitive decline, including identifying those who will develop an early dementia and motor progression in PD patients.

"The cumulative incidence of dementia associated with PD is approaching 80%, and individuals with PD are five to six times more likely to develop cognitive impairment than age-matched controls," explained lead investigator Gabriele Saretzki, PhD, Biosciences Institute, and The Ageing Biology Centre at the Campus for Ageing and Vitality of Newcastle University, Newcastle upon Tyne, UK. "PD is known to be associated with inflammation, and we have previously published data demonstrating that a more pro-inflammatory profile in the blood predicts more rapid clinical progression. In this new study, we sought to replicate this finding as well as to study markers of cell senescence (aging), a process that is known to be associated with inflammation and neurodegeneration."

• See Also: Comfort and satisfaction with care of home-dwelling dementia patients at the end of life

Investigators examined the association of blood-derived markers with motor and cognitive function over time to discover if this could help to better predict disease progression of newly diagnosed PD patients. More than 150 newly diagnosed PD patients who participated in the Cognitive Impairments in Cohorts with Longitudinal Evaluation-Parkinson's Disease (ICICLE-PD) study and 99 controls underwent physical and cognitive assessments over 36 months of follow-up.

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Researchers analyzed whether markers of cellular senescence such as telomere length (TL), p16 and p21 expression, as well as inflammatory markers in blood samples taken close to diagnosis can be predictive of cognitive and motor progression of the disease over the next 36 months. Mean leukocyte TL and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Investigators also selected five inflammatory markers from existing baseline data.
The study demonstrated that PD patients had shorter telomeres at baseline and 18 months later compared to age-matched healthy controls. Those PD patients, who had developed dementia after three years, also had significantly shorter telomeres compared to individuals who were dementia-free at this time. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months, while a simple inflammatory summary score at baseline best predicted cognitive score 36 months later in PD patients.
"The development of suitable blood-based biomarkers to predict outcomes is important for neurodegenerative diseases such as PD, which progress over many years," noted Dr. Saretzki. "The markers that we have identified need to be validated in further studies but could ultimately help with planning more targeted management for patients earlier in their disease course. Furthermore, a better understanding of the biological changes that predict disease course has implications for possible future therapies for the disease."
Co-investigator Roger Barker, MBBS, MRCP, Ph.D., Professor of Clinical Neuroscience and Honorary Consultant in Neurology at the University of Cambridge, and at Addenbrooke's Hospital, Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK, added: "Being able to reliably predict the clinical path a patient with newly diagnosed PD will follow would greatly help in terms of planning their treatment now and in the way we do trials of disease-modifying interventions in the future. This study provides an example of how this could be done using a simple blood sample."

• See Also: Gene ID’d as potential therapeutic target for dementia in Parkinson’s

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