UCLA scientists have uncovered a harmful group of immune cells that quietly builds up in aging tissues and in the livers of people with fatty liver disease:
When these cells were removed in mice, inflammation dropped sharply and liver damage was reversed, even though the animals continued eating an unhealthy diet.
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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.
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.”
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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.
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Although ABT-263 worked in mice, it is too toxic for widespread use in humans.