The aging liver undergoes significant changes in its functional organization and other key attributes, potentially increasing its vulnerability to disease. This revelation comes from a study led by researchers at Weill Cornell Medicine, suggesting that future therapies could block or reduce these changes, effectively rejuvenating the liver and enhancing its resilience against age-related chronic diseases.
Published on July 4 in the journal Hepatology, the study compared gene activity and other cellular characteristics in aged versus young mouse livers. The researchers observed notable aging-related changes, such as the enlargement of liver cells, inflammation, and the blurring of functional zones. Similar transformations were detected when comparing older and younger human livers.
Understanding Liver Aging
Dr. Robert Schwartz, the study’s senior author and an associate professor of medicine at Weill Cornell Medicine, highlighted the critical questions raised by these findings. “Do these changes underlie the aging liver’s reduced ability to metabolize drugs, neutralize toxins, and resist liver disease?” he asked. “That’s the big question we now intend to investigate.”
The liver plays a vital role in filtering blood and storing nutrients. Its regenerative capability has led to a perception that it is less affected by aging compared to other organs. However, chronic liver diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), become more prevalent with age. A recent study indicated that MASLD affects 30 to 40 percent of the U.S. population, with potential progression to severe inflammatory forms, cirrhosis, and cancer.
Innovative Research Techniques
Dr. Schwartz’s team employed advanced tools to examine the differences between aged and young livers. While the livers of two-year-old and two-month-old mice appeared similar in weight and overall appearance, microscopic analysis revealed that cells in aged livers were significantly larger, with notable deposits of lipofuscin, a substance associated with cellular damage in aging.
One of the study’s most striking findings emerged from single-nucleus RNA sequencing, a cutting-edge method that profiles gene activity across all cell types in a tissue sample. This research is considered the first to apply this technique to understanding liver aging. The resulting dataset on gene activity in tens of thousands of liver cells demonstrated that aging profoundly affects the functional organization or “zonation” of hepatocytes, the primary liver cell type.
“In young, healthy livers, hepatocytes perform distinct functions in distinct zones in the liver with different proximities to blood supply, but in aged livers this zonation is lost,” explained Dr. Saloni Sinha, the study’s first author and a postdoctoral research associate in the Schwartz laboratory. “We suspect this impairs the liver’s functions and its ability to respond to stress or injury.”
Implications for Future Therapies
The RNA sequencing revealed significant aging-related differences in the activity levels of hundreds of genes across various liver cell types. These differences included higher levels of inflammation and the presence of senescent cells, which are non-dividing and pro-inflammatory. Recent scientific insights suggest that the accumulation of such cells and associated inflammation—termed “inflammaging”—is a major driver of tissue aging and disease susceptibility.
The researchers confirmed the relevance of their mouse findings to human biology through similar observations in liver biopsies from younger and older individuals. The data generated in this study represent a valuable new resource for scientists researching liver biology. Dr. Schwartz, who is also affiliated with the Weill Cornell Medicine Sandra and Edward Meyer Cancer Center, and Dr. Sinha hope these insights will pave the way for new strategies to maintain liver health as it ages.
Looking Ahead
This groundbreaking study opens new avenues for understanding and potentially mitigating the effects of aging on the liver. As researchers continue to explore these findings, the possibility of developing therapies that could keep aged livers youthful and healthier becomes increasingly promising. The move represents a significant step forward in the fight against age-related liver diseases, offering hope for improved quality of life for aging populations.
