Salk Institute Identifies Acid Ceramidase as Novel Driver of Ferroptosis Vulnerability in Senescent Cells, Opening Path to Healthy Aging Therapeutics
核心洞察
Salk researchers discovered that senescent "zombie" cells express elevated acid ceramidase, making them hypersensitive to ferroptosis (搜索), an iron-dependent cell death pathway.
The vulnerability can spread from senescent cells to neighboring healthy cells through paracrine signaling, explaining how small populations of senescent cells drive tissue dysfunction.
Removing acid ceramidase protected both young and senescent cells from ferroptosis (搜索) via a novel lipid metabolism mechanism independent of iron or glutathione pathways.
A research team at the Salk Institute (搜索) has uncovered a previously unknown mechanistic link between cellular senescence and ferroptosis (搜索), revealing that the enzyme acid ceramidase drives ferroptosis sensitivity in aged cells and can transmit that vulnerability to surrounding healthy tissue. The findings, published in Cell Death and Disease on July 10, 2026, offer a dual-action therapeutic target that could simultaneously eliminate senescent cells while preserving neighboring tissue health.
The study, led by senior and co-corresponding author Pam Maher, PhD, a research professor at Salk who originally discovered the ferroptosis (搜索) pathway in 2001, examined human fetal lung WI-38 fibroblasts induced to senesce via replicative exhaustion. The team found that senescent cells expressed progressively higher levels of acid ceramidase, an enzyme that breaks down ceramides into sphingosine and free fatty acids, and that this elevation rendered the cells markedly more sensitive to RSL3-induced lipid peroxidation and ferroptosis compared to young, healthy cells.
"This is an entirely novel pathway that is independent of the mechanisms usually associated with ferroptosis (搜索)-induced cell death, as it doesn't involve any changes in iron or glutathione levels but instead modulates the lipid metabolism," said first author David Soriano-Castell, PhD, a postdoctoral researcher in Maher's lab.
A Contagious Vulnerability
One of the study's most striking findings was the cell non-autonomous nature of the ferroptosis (搜索) sensitivity. The Salk team demonstrated that vulnerable senescent cells could pass their susceptibility to neighboring non-senescent cells through paracrine signaling. This "contagious" spread of ferroptosis vulnerability helps explain how a relatively small population of senescent cells can progressively impact larger tissue areas over time, contributing to age-related dysfunction.
"We have unraveled a new mechanistic connection between ferroptosis (搜索) and senescence," Soriano-Castell explained. "This gives us a clear target that would eliminate two birds with one stone, eliminating senescent cells and keeping neighboring cells healthy for longer."
Protective Effect of Acid Ceramidase Removal
When the researchers removed acid ceramidase from both senescent and non-senescent cells, both populations became more resilient to induced ferroptosis (搜索). The protective effect operated through modulation of the polyunsaturated fatty acid composition of membrane phospholipids, a mechanism entirely distinct from the classic iron chelation or glutathione antioxidant pathways typically associated with ferroptosis regulation.
Translational Path to Healthy Aging
The findings carry significant translational potential. Experimental small-molecule drugs designed to inhibit acid ceramidase are already in development for other clinical applications, providing an immediate proof-of-concept framework for anti-aging drug discovery. The Salk team's work now positions these existing drug candidates for potential repurposing toward age-related conditions.
"Senescent cells are linked to many age-related conditions, including arthritis, poor wound healing, and neurodegenerative diseases like Alzheimer's or Parkinson's," said Maher. "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."
The United Nations projects that by 2050, the number of people over age 85 will triple globally, underscoring the urgency of extending healthspan—the number of years spent in good health—rather than merely lifespan.
"This is only the beginning," Soriano-Castell noted. "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."
The research was supported by the National Institutes of Health (grants AG069206 and AG095974) and the Bundy Foundation. Additional authors included Marie Goujon, Nawab John Dar, and Antonio Currais of Salk.