Scientists Find Way to Reverse Fatty Liver Disease Without Changing Diet

A newly identified population of dysfunctional immune cells may play a central role in both aging and chronic disease.

UCLA researchers have uncovered a rogue group of immune cells that may be quietly driving both aging and chronic liver disease.

These cells accumulate over time in tissues, especially in the liver, and appear to fuel persistent inflammation. When scientists removed them in mice, liver damage not only improved but was reversed, even though the animals continued eating an unhealthy diet.

The research, published in Nature Aging, focuses on cellular senescence. This process occurs when cells stop dividing but do not die. Instead, these lingering “zombie cells” remain in tissues and release a mix 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 a Longstanding Scientific Debate

For years, researchers questioned whether macrophages, the large immune cells that move through tissues clearing debris, pathogens, and dying cells, could actually become senescent. Most scientists believed they could not. One reason for the confusion is that healthy macrophages naturally show some features that resemble senescence, making it difficult to identify truly dysfunctional cells.

The UCLA team addressed this problem by identifying a clear molecular marker. They found that the presence of two proteins, p21 and TREM2, together signals macrophages that are truly senescent. These cells no longer function properly but continue to drive inflammation in nearby tissue.

Aging, Cholesterol, and Cellular Breakdown

Using this marker, the researchers observed a sharp increase in senescent macrophages with age. In the livers of mice, these cells rose from about 5% in young animals to roughly 60-80% in older ones. This increase closely matched the rise in chronic liver inflammation seen during aging.

The team also found that aging is not the only cause. High levels of cholesterol can push macrophages into a senescent state. In laboratory experiments, exposing healthy macrophages to elevated LDL cholesterol caused them to stop dividing, release inflammatory proteins, and display the 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 discovery raises a broader possibility that the researchers are now investigating. Diets high in fat and cholesterol may speed up biological aging by promoting macrophage senescence in multiple tissues, including the brain, heart, and body fat.

Reversing Liver Damage by Targeting Senescent Cells

To test whether removing these cells could improve health, the researchers treated mice with ABT-263, a drug that selectively kills senescent cells. The results were significant.

In mice on a high-fat, high-cholesterol diet, which models human metabolic liver disease, liver weight dropped from about 7% of total body weight to a healthier 4-5%. Overall body weight also fell by 25%, from about 40 grams (1.41 ounces) to around 30 grams (1.06 ounces). The treated livers were smaller and had a healthier red color compared to the enlarged, yellowish fatty livers of untreated mice.

These results show that removing senescent macrophages alone can lead to 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 Disease and Public Health Impact

To see if this mechanism applies to humans, the researchers analyzed an existing genomic dataset from liver biopsies. They found that the same senescent macrophage signature was much higher in diseased livers than in healthy ones. This suggests that macrophage senescence also plays a role in human chronic liver disease.

The findings are especially important in Los Angeles, where an estimated 30-40% of residents have fatty liver disease, with even higher rates in Latino communities. Current treatment options are limited, and early diagnosis often requires invasive methods.

“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 Safer Therapies and Broader Implications

Although ABT-263 works in mice, it is too toxic for widespread use in people. The research team is now working to identify safer drugs that can specifically remove senescent macrophages without harmful side effects.

They are also studying whether similar cells contribute to other age-related diseases, such as cancer and neurodegenerative disorders. In the brain, microglia, which are the macrophages of the central nervous system, may also become senescent in conditions like Alzheimer’s disease as they are exposed to large amounts of cellular debris.

Overall, the researchers believe their findings support the geroscience hypothesis. This idea suggests that a single underlying process of aging, in this case, the buildup of senescent macrophages, may contribute to many diseases that affect health and lifespan.

“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.”

Reference: “p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease” by Ivan A. Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C. Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y. Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A. Soto, Alexander J. Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D. J. Lopez Gonzalez, Matthew R. Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M. Koehler, Jesse G. Meyer, Julia J. Mack, Charles Brenner, Steven J. Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J. Lusis and Anthony J. Covarrubias, 16 April 2026, Nature Aging.
DOI: 10.1038/s43587-026-01101-6

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.

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