In young mice, only about 5% of liver macrophages carry the molecular signature of senescence. In older mice, that figure climbs to between 60 and 80%. These cells do not merely accumulate. They actively degrade the tissue around them.
UCLA researchers have identified this population of "zombie" immune cells as a driver of fatty liver disease and possibly of aging itself. The findings, published in Nature Aging, center on macrophages that have entered cellular senescence, a state in which cells stop dividing but refuse to die, continuing to release inflammatory signals that damage neighboring tissue.
For years, scientists debated whether macrophages could become senescent at all. Healthy macrophages already display some molecular features resembling senescence, making the two states difficult to distinguish. The UCLA team resolved this by identifying a specific combination of two proteins, p21 and TREM2, that reliably marks macrophages that are truly senescent and no longer functioning properly.
Anthony Covarrubias, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA:
"Senescent cells are fairly rare, but think of them like a broken-down car on the 405. Just one stalled car can back up traffic for miles. Now imagine five or ten of them slowly accumulating. That's what these cells do to a tissue: even a small number causes enormous disruption."
The researchers found that excess cholesterol, not just aging, pushes macrophages into this destructive state. When healthy macrophages were exposed to high levels of LDL cholesterol in laboratory conditions, they stopped dividing, began releasing inflammatory proteins, and displayed the same p21-TREM2 signature.
Ivan Salladay-Perez, first author of the study and a graduate student in the Covarrubias lab:
"Physiologically, macrophages can handle cholesterol metabolism. But in a chronic state, it's pathological. And when you look at fatty liver disease, which is driven by overnutrition and too much cholesterol in the blood, that excess cholesterol appears to be a major driver of the senescent macrophage population."
To test whether removing these cells could reverse damage, the team treated mice with ABT-263, a drug that selectively eliminates senescent cells. In mice fed a high-fat, high-cholesterol diet, liver size dropped from about 7% of body weight to a healthier 4-5%. Body weight fell by roughly 25%, from about 40 grams to around 30 grams. The treated livers appeared smaller and healthier, with normal red coloration, compared to the enlarged, yellowish livers of untreated animals.
Salladay-Perez:
"That's what wowed me. Eliminating senescent cells doesn't just slow the fatty liver, it actually reverses it."
The researchers also analyzed genomic data from human liver biopsies and found that the same senescent macrophage signature was significantly elevated in diseased livers compared to healthy ones. In Los Angeles, where 30-40% of residents are affected by fatty liver disease, with higher rates in Latino communities, treatment options remain limited and early detection tools are lacking.
ABT-263 is too toxic for widespread human use. The research team plans to screen for safer compounds that can selectively remove senescent macrophages without harmful side effects. They are also investigating whether similar processes occur in other age-related diseases, including whether microglia, the macrophages of the central nervous system, become senescent in conditions like Alzheimer's disease.
The findings align with the geroscience hypothesis, which proposes that a single underlying aging process can drive multiple diseases. The buildup of senescent macrophages may contribute not only to fatty liver disease but also to atherosclerosis, Alzheimer's, and cancer.
DOI: 10.1038/s43587-026-01101-6