Summary: A new study from the Salk Institute shows that senescent, or “zombie,” cells produce elevated amounts of the enzyme acid ceramidase. This increase reshapes lipid metabolism and makes senescent cells much more vulnerable to ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. The researchers also found that senescent cells can transmit this ferroptosis susceptibility to neighboring healthy cells through acid ceramidase–related signaling. These findings reveal a promising metabolic target to selectively remove damaged cells while protecting surrounding tissue, with immediate translational potential because experimental acid ceramidase inhibitors already exist.
Because small-molecule inhibitors of acid ceramidase have been developed for other clinical applications, these results create a near-term framework for designing therapies aimed at extending human healthspan.
Key Facts
- Enzymatic driver of vulnerability: Replicative senescent human lung cells express progressively higher levels of acid ceramidase, which sensitizes them to induced ferroptosis compared with young, non-senescent cells.
- Contagious susceptibility: Senescent cells can confer ferroptosis vulnerability to neighboring healthy cells, helping explain how a small number of damaged cells can promote widespread tissue dysfunction during aging.
- Independent of iron or glutathione changes: The protective effect of removing acid ceramidase operates via lipid metabolism and does not depend on altering cellular iron or glutathione antioxidant levels.
- Translational opportunity: Existing experimental drugs that inhibit acid ceramidase offer a ready proof-of-concept to pursue anti-aging therapies that target this pathway.
- Dual therapeutic potential: Targeting acid ceramidase could both eliminate harmful senescent cells and preserve the resilience of surrounding healthy tissue.
Source: Salk Institute
Our population is aging. The United Nations projects that by 2050 the number of people over age 85 will roughly triple. A longer lifespan does not automatically mean a longer healthspan—the period of life spent in good health. Salk Institute researchers are investigating cellular mechanisms that drive age-related decline to help extend healthy years.
In this study, investigators examined two cellular processes that increase with age: senescence, where cells stop dividing but remain metabolically active, and ferroptosis, a regulated cell death pathway caused by uncontrolled lipid peroxidation. Working with human lung fibroblasts, the team discovered that higher acid ceramidase expression in senescent cells alters membrane lipid composition and heightens sensitivity to ferroptosis, and that this vulnerability can be communicated to nearby non-senescent cells.
The fact that acid ceramidase is already being targeted by experimental therapies in other disease contexts makes it an attractive and actionable target for developing interventions aimed at preserving tissue health during aging.
The study was published in Cell Death and Disease on July 10, 2026.
“Senescent cells are implicated in many age-related conditions, from impaired wound healing and arthritis to neurodegenerative disorders such as Alzheimer’s and Parkinson’s,” says Pam Maher, PhD, senior and co-corresponding author and research professor at Salk. “These findings mark an important step toward therapeutic strategies that could address multiple age-associated diseases by targeting a single metabolic vulnerability.”
What are ferroptosis and senescence?
Ferroptosis is an iron-dependent form of regulated cell death driven by the build-up of lipid peroxides in cellular membranes. Normally, antioxidants like glutathione help prevent lipid peroxidation and preserve cell viability. Pam Maher, who first described and named the oxytosis pathway in 2001, has continued to study connections between lipid peroxidation, iron dysregulation, and neurodegeneration. Separate work from her laboratory links chronic iron exposure in neurons to reduced resilience and increased vulnerability to neurodegenerative processes.
Cellular senescence refers to a stable arrest of cell division in which cells remain metabolically active and often secrete inflammatory or tissue-remodeling factors. These so-called “zombie” cells accumulate with age. While senescence can be beneficial in some contexts (for example, in wound repair), persistent senescent cells contribute to tissue dysfunction and disease risk.
Are ferroptosis and senescence connected during aging?
To explore overlap between these processes, the researchers induced replicative senescence in human WI-38 lung fibroblasts and then tested their response to ferroptosis-inducing agents. Senescent cells were substantially more sensitive to ferroptosis than proliferating cells. This increased sensitivity correlated with progressive upregulation of acid ceramidase—an enzyme that converts ceramides into sphingosine and free fatty acids and thereby alters the composition of membrane phospholipids.
When the team reduced or removed acid ceramidase from both young and senescent cells, the cells became more resistant to ferroptosis. Importantly, this protective effect occurred without detectable changes in cellular iron content or glutathione levels, indicating a novel, lipid-centered mechanism of ferroptosis regulation.
The researchers also observed a paracrine effect: senescent cells could make nearby healthy cells more susceptible to ferroptosis. This cell non-autonomous sensitization helps explain how a small number of senescent cells can drive spreading tissue deterioration over time.
“We’ve revealed a new mechanistic link between ferroptosis and senescence,” says first author David Soriano-Castell, PhD. “Targeting acid ceramidase offers a strategy to both remove harmful senescent cells and protect neighboring cells, an approach that could slow age-related tissue decline.”
How could this advance healthy aging?
Because experimental inhibitors of acid ceramidase already exist, the findings present an immediate therapeutic hypothesis: drugs designed to block this enzyme might selectively eliminate senescent cells or reduce their harmful influence on tissues, thereby extending healthspan. The next steps include mapping the full pathway in animal models and exploring translational studies that could lead to clinical trials.
“This work is an early but promising foundation,” Soriano-Castell adds. “Acid ceramidase is targetable, and building on existing efforts could accelerate development of interventions that promote tissue resilience during aging.”
“The more we learn about ferroptosis,” Maher concludes, “the more opportunities arise for healthy aging innovations. We’ll continue to investigate how modulating ferroptosis-related lipid metabolism can benefit longevity and resilience.”
Other authors and funding
Other contributors to the study include Marie Goujon, Nawab John Dar, and Antonio Currais of the Salk Institute. Funding was provided by the National Institutes of Health (AG069206, AG095974) and the Bundy Foundation.
Key Questions Answered:
A: Cellular senescence is a permanent arrest of cell division where cells persist and often secrete inflammatory factors, while ferroptosis is a regulated form of cell death caused by toxic accumulation of lipid peroxides in membranes.
A: Increased acid ceramidase changes the lipid composition of membrane phospholipids—particularly polyunsaturated fatty acids—making cells more prone to lipid peroxidation and ferroptosis. Inhibiting or removing the enzyme increases resistance without altering iron or glutathione levels.
A: It explains how a small population of senescent cells can initiate a cascade of dysfunction across tissue by sensitizing neighboring cells to ferroptosis, and it identifies a targetable mechanism to block that spread and protect tissue health.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was added by the newsroom team.
About this aging and neuroscience research news
Author: Salk Communications
Source: Salk Institute
Contact: Salk Communications – Salk Institute
Image: Image credited to Neuroscience News
Original Research: Open access. “Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in WI-38 replicative senescent cells” by David Soriano-Castell, Marie Goujon, Nawab John Dar, Antonio Currais & Pamela Maher. Cell Death and Disease. DOI: 10.1038/s41419-026-09108-y
Abstract
Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in WI-38 replicative senescent cells
Cellular senescence involves irreversible cell cycle arrest and the senescence-associated secretory phenotype, making senescent cells a key target for therapies addressing age-related diseases. Ferroptosis is an iron-dependent regulated cell death process driven by membrane lipid peroxidation and has been linked to age-associated disorders.
Using human fetal lung WI-38 fibroblasts driven into replicative senescence, this study identifies acid ceramidase (ACase) as a regulator that breaks down ceramides into sphingosine and free fatty acids and thereby alters membrane polyunsaturated fatty acid composition. Elevated ACase levels sensitize senescent cells to RSL3-induced lipid peroxidation and ferroptosis. The authors also demonstrate that senescent cells can paracrinally sensitize neighboring non-senescent cells to ferroptosis. These findings position acid ceramidase as a novel regulator of ferroptosis and highlight therapeutic opportunities for targeting senescence-associated disorders to advance healthy aging strategies.