A study led by UCLA scientists reveals that targeting dysfunctional immune cells may reverse fatty liver disease, offering new insights into chronic inflammation and aging.
Los Angeles, CA – In a significant advancement in the understanding of fatty liver disease, researchers at the University of California, Los Angeles (UCLA) have identified a population of dysfunctional immune cells that contribute to chronic inflammation and liver damage. Their findings indicate that removing these cells can reverse liver damage in mice, even when dietary habits remain unchanged. The study, published in the journal Nature Aging, highlights the role of cellular senescence in both aging and chronic disease.
The Role of Senescent Cells
Cellular senescence occurs when cells halt division but do not die, resulting in what are commonly referred to as ‘zombie cells.’ These senescent cells accumulate in tissues over time and release inflammatory signals that can harm surrounding healthy cells. According to Anthony Covarrubias, senior author of the study and affiliated with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, “Senescent cells are fairly rare, but think of them like a broken-down car on the 405. 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.”
Uncovering the Mechanism
For years, the scientific community debated whether macrophages, the immune cells responsible for clearing debris and pathogens, could enter a senescent state. This confusion stemmed from the fact that healthy macrophages exhibit characteristics similar to senescent cells, complicating their identification. The UCLA team overcame this challenge by establishing a definitive molecular marker for senescent macrophages, specifically the presence of two proteins, p21 and TREM2. These markers indicate that the macrophages have ceased functioning effectively while continuing to promote inflammation.
The researchers found that the proportion of senescent macrophages in the liver of mice increased dramatically with age, from approximately 5% in young mice to between 60-80% in older mice. This rise parallels the increase in chronic liver inflammation associated with aging. Additionally, high cholesterol levels were identified as another factor that could induce macrophage senescence, with laboratory experiments showing that exposure to elevated levels of low-density lipoprotein (LDL) cholesterol caused healthy macrophages to become dysfunctional.
Significant Health Improvements in Mice
To explore the potential health benefits of removing senescent cells, the researchers administered ABT-263, a drug designed to selectively eliminate these cells, to mice on a high-fat, high-cholesterol diet. The results were promising: liver weight in treated mice decreased from approximately 7% of total body weight to a healthier 4-5%. Overall body weight also dropped by 25%, showcasing significant improvements in liver health. The treated livers appeared smaller and exhibited a healthier coloration compared to untreated mice, which displayed enlarged, yellowish fatty livers. Ivan Salladay-Perez, the first author of the study, remarked, “That’s what wowed me. Eliminating senescent cells doesn’t just slow the fatty liver — it actually reverses it.”
Implications for Human Health
To assess whether these findings could translate to human health, the researchers analyzed genomic data from liver biopsies and discovered that the senescent macrophage signature was significantly elevated in diseased livers compared to healthy ones. This suggests a similar role for macrophage senescence in human chronic liver disease, an issue particularly relevant in Los Angeles, where an estimated 30-40% of residents suffer from fatty liver disease. The prevalence is even higher in Latino communities, emphasizing the urgent need for effective treatment options.
Covarrubias stated, “This is a huge public health crisis in the making. 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.”
Future Directions and Broader Applications
While the drug ABT-263 has shown efficacy in mice, its toxicity prohibits its use in humans. The research team is now focused on identifying safer alternatives that can selectively target senescent macrophages without adverse effects. They are also exploring the role of similar senescent cells in other age-related conditions, including cancer and neurodegenerative diseases, such as Alzheimer’s disease, where microglia, the brain’s macrophages, may also become senescent.
Overall, the findings support the geroscience hypothesis, which posits that a common underlying process of aging contributes to various diseases affecting health and longevity. Salladay-Perez concluded, “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. It all goes back to understanding how these cells arise in the first place.”
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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