The research, published in Nature Aging, focuses on cellular senescence, a process triggered by stress in which cells stop dividing but do not die. These lingering cells, often called “zombie cells,” remain active in tissues and release a steady stream of inflammatory signals that can damage surrounding cells.

“Senescent cells are fairly rare, but think of them like a broken-down car on the 405,” said 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. “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.”

Solving the Macrophage Mystery

For years, researchers questioned whether macrophages, the immune cells that patrol the body and clean up debris, could truly become senescent. Many believed they could not. One reason for the confusion is that healthy macrophages already show some of the same molecular features seen in senescent cells, making it difficult to distinguish between normal and dysfunctional states.

The UCLA team addressed this problem by identifying a clear molecular signature. They found that the combination of two proteins, p21 and TREM2, reliably marks macrophages that are truly senescent and no longer functioning properly, while still driving inflammation in nearby tissue.

Using this marker, the researchers observed a dramatic shift with age. In young mice, only about 5% of liver macrophages were senescent. In older mice, that number rose to between 60 and 80%, closely matching the increase in chronic liver inflammation seen with aging.

Cholesterol as a Key Trigger

Aging is not the only factor behind this buildup. The researchers discovered that excess cholesterol can also push macrophages into a senescent state. When healthy macrophages were exposed to high levels of LDL cholesterol in the lab, they stopped dividing, began releasing inflammatory proteins and displayed the same p21-TREM2 signature.

“Physiologically, macrophages can handle cholesterol metabolism,” said Ivan Salladay-Perez, first author of the new study and a graduate student in the Covarrubias lab. “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.”

This raises a broader possibility that diets high in fat and cholesterol may speed up biological aging by promoting macrophage senescence not only in the liver, but also in other organs such as the brain, heart and fat tissue.

Clearing Senescent Cells Reverses Liver Damage

To test whether removing these cells could improve health, the team treated mice with ABT-263, a drug designed to selectively eliminate senescent cells. The effects were dramatic. In mice fed a high-fat, high-cholesterol diet, liver size dropped from about 7% of body weight to a healthier 4-5% percent. Body weight also fell by about 25%, decreasing from roughly 40 grams to around 30 grams.

The treated livers appeared smaller and healthier, with a normal red color, compared to the enlarged, yellowish livers seen in untreated animals.

The results suggest that removing senescent macrophages alone can produce major metabolic improvements, even without changing diet. “That’s what wowed me,” said Salladay-Perez. “Eliminating senescent cells doesn’t just slow the fatty liver — it actually reverses it.”

Evidence in Human Liver Disease

To explore whether the findings apply to people, the researchers analyzed an existing genomic dataset from human liver biopsies. They found that the same senescent macrophage signature was significantly higher in diseased livers than in healthy ones. This suggests that macrophage senescence may also contribute to chronic liver disease in humans.

The issue is especially pressing in Los Angeles, where an estimated 30-40% of residents are affected by fatty liver disease, with even higher rates in Latino communities. Treatment options remain limited, and early detection tools are still lacking.

“This is a huge public health crisis in the making,” said Covarrubias, who is also an assistant professor of microbiology, immunology and molecular genetics. “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.”

Toward New Treatments and Broader Impact

Although ABT-263 worked in mice, it is too toxic for widespread use in humans. 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. In the brain, for example, microglia, which are the macrophages of the central nervous system, may become senescent in conditions like Alzheimer’s disease as they encounter large amounts of cellular debris.

A Shared Mechanism of Aging and Disease

The findings support the geroscience hypothesis, which proposes that a single underlying process of aging can drive multiple diseases. In this case, the buildup of senescent macrophages may contribute to conditions ranging from fatty liver disease to atherosclerosis, Alzheimer’s and cancer.

“If you really understand the basic mechanisms driving inflammation with aging, you can target those same mechanisms to treat not just fatty liver disease, but atherosclerosis, Alzheimer’s and cancer,” said Salladay-Perez. “It all goes back to understanding how these cells arise in the first place.”

The study was supported by the National Institutes of Health, the Glenn Foundation for Medical Research, the American Federation for Aging Research and the UCLA-UCSD Diabetes Research Center.