UCLA researchers announced on Apr. 16 the discovery of a specific group of immune cells that accumulate in aging tissues and in the livers of people with fatty liver disease. The study, published in Nature Aging, found that removing these cells reduced inflammation and reversed liver damage in mice, even when they continued eating an unhealthy diet.
This research could have significant implications for treating age-related diseases and conditions like fatty liver disease, which affects a large portion of the population. The findings may help scientists develop new therapies targeting these dysfunctional cells.
The team focused on cellular senescence—a process where stressed cells stop dividing but do not die. These "zombie cells" remain active in tissues, releasing inflammatory signals. Anthony Covarrubias, senior author and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, said: "Senescent cells are fairly rare, but think of them like a broken-down car on the 405." For years it was unclear if macrophages—immune system patrols—could become senescent because healthy macrophages naturally show some markers associated with this state.
The UCLA team identified two proteins (p21 and TREM2) as a reliable signature for genuinely senescent macrophages. Using this marker, they observed that senescent macrophages increase significantly with age or excess cholesterol exposure in mice livers. Ivan Salladay-Perez, first author and graduate student at UCLA, said: "Physiologically, macrophages can handle cholesterol metabolism... But in a chronic state it's pathological." He added that excess cholesterol is likely driving more macrophages into dysfunction among those with fatty liver disease.
When treated with ABT-263—a drug triggering death only in senescent cells—mice saw dramatic improvements: lower body weight and healthier livers despite staying on high-fat diets. Salladay-Perez said: "Eliminating senescent cells doesn't just slow the fatty liver - it actually reverses it." Analysis of human data also showed higher levels of these dysfunctional immune cells among people with diseased livers compared to healthy ones.
Covarrubias noted the urgency given Los Angeles' high rates of fatty liver disease: "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..." While ABT-263 is too toxic for humans currently, further studies will seek safer compounds to target these harmful immune cells.
