Not all zombie skin cells are the same. New research reveals three unique subtypes with different roles in aging and disease, offering hope for targeted treatments that eliminate the bad while keeping the good.
Senescent skin cells, often called “zombie cells” because they stop dividing but don’t die, have long been a mystery. These cells can be harmful, driving inflammation and age-related diseases, yet they also play helpful roles, such as assisting in wound healing.
Now, new research may help explain this contradiction: not all senescent skin cells are the same.
Scientists at Johns Hopkins University have discovered that senescent skin cells fall into three distinct subtypes, each with unique shapes, molecular markers, and functions. This discovery could enable researchers to selectively eliminate the harmful cells while preserving the beneficial ones.
The study was published today (April 25) in the journal Science Advances.
Same Cell Type, Different Paths
“We’ve known that senescent skin cells are different from senescent immune cells or senescent muscle cells. But within a cell type, senescent cells are often considered the same—in essence, skin cells are either senescent or not, for example,” said Jude Phillip, an assistant professor of biomedical engineering at Johns Hopkins University. “But we’re finding that when a skin cell goes into senescence, or a zombie-like state, the cell could go down one of three different paths, each leading to a slightly different subtype.”
Deep Data from Decades of Aging Research
Leveraging new advances in machine learning and imaging technology, the researchers compared skin cell samples from 50 healthy donors between the ages of 20 and 90 who participated in the Baltimore Longitudinal Study, an NIH-funded project that is the longest ongoing study of aging in the United States.
Researchers extracted fibroblasts—cells that produce the scaffolding to give tissues their structure— associated with skin tissue and pushed them toward senescence by damaging their DNA, something that happens with aging. Because senescent cells build up naturally as people grow older, the aged samples contained a mix of healthy/nonsenescent and senescent fibroblasts.
Mapping Cell Identity with Imaging and AI
Using specialized dyes, the researchers were able to capture images of the cells’ shapes and stained elements that are known to indicate senescent cells. Algorithms developed for this study analyzed the images, measured 87 different physical characteristics for each cell, and sorted the fibroblasts into groups.
Fibroblasts come in 11 different shapes and sizes, three of which are distinct to senescent skin cells, the researchers found. Only one subtype of senescent fibroblast, which the researchers named C10, was more prevalent in older donors.
Some Drugs Hit, Others Miss
In the petri dishes, each subtype responded differently when exposed to existing drug regimens designed to target and kill zombie cells. Dasatinib + Quercetin, a drug being tested in clinical trials, for example, most effectively killed C7 senescent fibroblasts but was limited in killing the age-associated C10 senescent fibroblasts.
Though further research is needed to verify which fibroblast subtype is harmful and which is helpful, the findings show that drugs can target one subtype and not the others.
“With our new findings, we have the tools ready to develop new drugs or therapies that preferentially target the senescence subtype that drives inflammation and disease as soon as it is identified,” Phillip said.
Implications for Cancer Treatment
More precise targeting of senescence could benefit cancer treatments, the researchers said.
Certain therapies are being designed to trigger senescence in cancer cells, converting uncontrollably replicating cancer cells into dead-in-the-water zombie cells. While these therapies could stop tumor growth, they leave senescent cells in their wake. Conventional chemotherapies also push cells like fibroblasts toward senescence as a side effect. The buildup of senescent cells during treatment can be problematic as those cells may promote inflammation at a time when a patient’s immune system is at its most vulnerable.
Clearing the Chemo Aftermath
Patients may benefit from a drug administered after chemotherapy that can sweep up the mess, removing harmful senescent cells while leaving behind the helpful senescent cells. These types of drugs are called senotherapies.
Next, the researchers plan to look at senescence subtypes in tissue samples, not just in flasks and petri dishes, to see how those subtypes might be associated with various skin diseases and age-associated diseases.
“We hope, with some more development, our technology will be used to help predict which drugs might work well for targeting senescent cells that contribute to specific diseases,” Phillip said. “Eventually, the dream is to be able to provide more information in a clinical setting to help with individual diagnoses and boost health outcomes.”
Reference: “Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts” by Pratik Kamat, Nico Macaluso, Yukang Li, Anshika Agrawal, Aaron Winston, Lauren Pan, Teasia Stewart, Bartholomew Starich, Nicholas Milcik, Chanhong Min, Pei-Hsun Wu, Jeremy Walston, Jean Fan and Jude M. Phillip, 25 April 2025, Science Advances.
DOI: 10.1126/sciadv.ads1875
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