“Zombie” immune cells may help drive steatotic liver disease, study shows
Clearing damaged macrophages reduced liver inflammation, fat in mice
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Clearing senescent macrophages, a type of damaged immune cell that doesn’t die off as it should, reduced inflammation and reversed signs of liver fat buildup in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD), a form of steatotic liver disease (SLD), a study showed.
“That’s what wowed me,” Ivan Salladay-Perez, the study’s first author and a graduate student at the University of California, Los Angeles (UCLA), said in a university news story. “Eliminating senescent cells doesn’t just slow the [MASLD] — it actually reverses it.”
Anthony Covarrubias, PhD, the study’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, said: “We’re seeing [SLD] 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 study, “p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease,” was published in Nature Aging.
Damaged immune cells may fuel MASLD
MASLD is a form of SLD defined by steatosis, or abnormally high amounts of fat in the liver, in the presence of certain cardiometabolic risk factors, including obesity, high blood sugar, high blood pressure, and high cholesterol levels.
Senescent cells, often called “zombie cells,” are damaged cells that stop dividing but don’t die off when they should. They can accumulate with age and are associated with inflammation, tissue damage, and age-related diseases. As such, there’s growing interest in targeting senescent cells therapeutically.
“Senescent cells are fairly rare, but think of them like a broken-down car,” said Covarrubias, who is also an assistant professor of microbiology, immunology and molecular genetics 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.”
Macrophages are specialized immune cells that patrol the body and engulf, or “eat,” microbes, dead cells, and debris. These cells naturally show some molecular markers of senescence, making it difficult to distinguish healthy macrophages from truly senescent ones.
“The rising prevalence of global aging in parallel with an obesity epidemic underscores the need to investigate the role of senescent macrophages in driving chronic inflammation and metabolic dysfunction associated with aging,” the researchers wrote. Therefore, they set out to “test the hypothesis that macrophages represent a major source of senescent cells in aging tissues and act as key drivers of inflammaging.”
Inflammaging refers to chronic, sterile, or infection-free, low-grade inflammation that develops with advanced age.
Researchers identify markers of senescent macrophages
The team first exposed lab-grown mouse macrophages to DNA-damaging agents to test whether the cells could undergo an irreversible and stable form of senescence. They found that macrophages producing two proteins, p21 and TREM2, were genuinely senescent. These cells also activated inflammatory pathways related to type I interferons, a family of immune signaling proteins.
Kupffer cells, the liver’s resident macrophages, showed the most pronounced age-dependent increase in senescence markers.
These senescent macrophages were found to be enriched in fatty molecules, including cholesterol. When the team loaded cholesterol into healthy macrophages, the cells began producing p21 and TREM2, indicating that they had become senescent.
“Physiologically, macrophages can handle cholesterol metabolism,” Salladay-Perez said. “But in a chronic state, it’s [disease-causing]. And when you look at [MASLD], 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.”
Young and aged mice were then treated with ABT-263, a drug that triggers death in senescent cells. In the liver, the proportion of senescent macrophages increased from roughly 5% in young mice to roughly 50% in aged mice, and ABT-263 reduced this proportion to about 10% in aged mice.
While ABT-263 was effective in mice, the UCLA team noted that it is too toxic for broad use in people. As a next step, the researchers plan to screen for compounds that can selectively eliminate senescent macrophages without side effects.
Clearing senescent cells reduces liver fat in mice
Building on these findings, the team examined a mouse model fed a high-fat, high-cholesterol diet to induce MASLD. When these mice were treated with ABT-263 after about three months on the diet, they showed a significant reduction in body weight without changes in food intake, as well as reductions in liver weight and lower blood levels of an inflammatory molecule called TNF.
Livers of treated mice appeared smaller and darker red, in contrast to the enlarged, yellow, fat-rich appearance of untreated control livers. In line with these results, tissue analysis showed a reduction in steatosis, or liver fat buildup.
When the researchers analyzed publicly available liver biopsy data from people with cirrhosis, or irreversible liver scarring, and healthy controls, they found that the same senescent macrophage signature was markedly elevated in diseased livers.
“These findings establish macrophage senescence as a central driver of chronic inflammation in aging and [MASLD], and a tractable therapeutic target,” the researchers wrote.
The team is also exploring whether similar cells play a role in other age-related diseases. Salladay-Perez added: “If you really understand the basic mechanisms driving inflammation with aging, you can target those same mechanisms to treat not just [SLD], but … Alzheimer’s and cancer. It all goes back to understanding how these cells arise in the first place.”
