UCLA researchers announced on Apr. 16 the discovery of a population of dysfunctional immune cells, called “zombie macrophages,” that accumulate in the liver during aging and fatty liver disease, leading to chronic inflammation in both conditions.
This finding is significant because it suggests a new potential target for treating fatty liver disease, which affects an estimated 30-40% of Los Angeles residents. The study found that excess dietary cholesterol can push these immune cells into a permanently inflamed state, indicating that high-cholesterol diets may speed up biological aging at the cellular level.
The research team identified a molecular signature—two proteins named p21 and TREM2—that reliably marks senescent macrophages. Using this marker, they observed that the proportion of these dysfunctional cells increases from about 5% in young mice to nearly 60-80% in older ones. When healthy macrophages were exposed to high levels of LDL cholesterol in laboratory tests, they developed features of senescence and began secreting inflammatory proteins. “Physiologically, macrophages can handle cholesterol metabolism,” said Ivan Salladay-Perez, first author and graduate student at UCLA. “But in a chronic state, it’s pathological. And when you look at fatty liver disease…that excess cholesterol appears to be a major driver of the senescent macrophage population.” Senior author Anthony Covarrubias added: “Senescent cells are fairly rare, but think of them like a broken-down car on the 405…even a small number causes enormous disruption.”
To test possible treatments, mice with diet-induced metabolic liver disease were given ABT-263—a drug targeting senescent cells—which reduced their liver weight and overall body weight even without dietary changes. Salladay-Perez said: “Eliminating senescent cells doesn’t just slow the fatty liver—it actually reverses it.” Analysis of human genomic data also showed elevated markers for these zombie macrophages in diseased livers compared to healthy ones.
The findings highlight an urgent public health issue as there are few treatments or early diagnostic tools for fatty liver disease today. Covarrubias said: “We’re seeing fatty liver disease in younger and younger people…So we’re really happy to make some inroads into understanding what’s driving it and identifying cell types we might be able to target.” The team plans further drug screening studies for safer compounds that selectively eliminate these problematic immune cells.
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Looking ahead, researchers are exploring whether similar processes occur elsewhere in the body—including conditions like Alzheimer’s—and plan further studies on drugs targeting these zombie immune cells.
