The study, published in Nature Aging, focuses on cellular senescence a process where damaged cells stop dividing but persist and release inflammatory signals. Researchers led by Anthony Covarrubias at University of California, Los Angeles identified that certain macrophages can become truly senescent, contributing to tissue dysfunction despite their small numbers. They resolved longstanding uncertainty by discovering a distinct molecular signature combining the proteins p21 and TREM2 that accurately identifies these harmful, inflammation driving cells.

Using this molecular signature, researchers found that senescent macrophages in the liver increase dramatically with age from about 5% in young mice to as much as 60–80% in older ones mirroring rising chronic inflammation. The study, published in Nature Aging, also showed that high levels of LDL cholesterol can trigger this senescent state, causing macrophages to stop dividing and release inflammatory signals. According to Ivan Salladay-Perez and Anthony Covarrubias at University of California, Los Angeles, excess cholesterol particularly in conditions like fatty liver disease appears to be a key driver, raising the possibility that high-fat, high-cholesterol diets may accelerate aging processes across multiple organs.

Targeting senescent cells showed promising therapeutic potential, as researchers treated mice with ABT-263, a drug that selectively eliminates senescent cells. Reported in Nature Aging, the treatment significantly reduced liver size, body weight, and fat accumulation in mice with diet induced liver disease even without changing their diet effectively reversing liver damage. According to Ivan Salladay Perez, this demonstrates that removing senescent macrophages can do more than slow disease progression; it can reverse it. Supporting its relevance to humans, the same senescent cell signature was found to be elevated in liver biopsy data from patients with chronic liver disease. These findings are particularly important given the high prevalence of fatty liver disease in regions like Los Angeles, where effective treatments and early diagnostic tools remain limited.

Anthony Covarrubias of University of California, Los Angeles described fatty liver disease as an escalating public health concern, increasingly affecting younger populations. While ABT-263 showed strong results in mice, its toxicity limits human use, prompting ongoing efforts to identify safer drugs that can selectively eliminate senescent macrophages. The research team is also investigating whether similar mechanisms contribute to other age related conditions, including cancer and neurodegenerative diseases like Alzheimer’s disease, where brain immune cells may also become senescent. These findings support the geroscience hypothesis, suggesting that a common aging mechanism such as the buildup of senescent immune cells may drive multiple chronic diseases, opening pathways for broader therapeutic strategies targeting inflammation and aging at their root.

source: https://newsroom.ucla.edu/releases/zombie-immune-cells-driver-fatty-liver-disease-inflammation-aging