The aging liver undergoes dramatic changes in its functional organization and other key attributes, which may underpin its increasing susceptibility to disease, according to a study led by investigators at Weill Cornell Medicine. The findings suggest the possibility of future therapies that would block or reduce such changes to treat or prevent age-related chronic liver diseases—effectively making the liver more youthful and resilient.

In the study, published in Hepatology, the researchers compared gene activity and other features of the cells in aged versus young mouse livers. Among the major aging-related changes they observed were enlargements of many liver cells, inflammation and blurring of the functional zones of normal livers. The researchers observed similar changes when comparing older and younger human livers.

“Do these changes underlie the aging liver’s reduced ability to metabolize drugs, neutralize toxins and resist liver disease?” said study senior author Dr. Robert Schwartz, an associate professor of medicine and the Irma Hirschl Trust Research Award Scholar at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center. “That’s the big question we now intend to investigate.”

The liver’s essential functions include filtering the blood and storing metabolites and nutrients. It does have the ability to regenerate itself, which has encouraged the view that it is less affected by aging than other organs. But chronic liver diseases, especially metabolic dysfunction-associated steatotic liver disease (MASLD), are more likely to develop as people age, and in general are extremely common—one recent study suggested that the condition affects 30% to 40% of the U.S. population. MASLD can also develop into severe, inflammatory forms leading to cirrhosis and cancer. Yet the molecular underpinnings of such age-related liver conditions are poorly understood.

In the study, Dr. Schwartz’s team used a variety of tools to take a fresh look at the differences between aged and young livers. While the livers of two-year- and two-month-aged mice were similar in weight and overall appearance, comparison under a microscope showed that the cells in aged livers were much larger on average, with marked deposits of lipofuscin, a substance known to accumulate in, and potentially damage, aging cells.

Some of the most striking findings came from single-nucleus RNA sequencing, a relatively new method that allows scientists to profile gene activity in essentially all cell types in a tissue sample. This study is thought to be the first that applies the technique to understand liver aging. The resulting dataset on gene activity in tens of thousands of liver cells revealed that aging has a strong impact on the usual functional organization or “zonation” of hepatocytes, the main type of liver cell.

“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,” said study first author Dr. Saloni Sinha, 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.”

The RNA sequencing showed that there are significant aging-related differences in the activity levels of hundreds of genes in dozens of distinct liver cell types. Analyses of these differences pointed, among other things, to higher levels of inflammation and the non-dividing, pro-inflammatory cell state known as senescence. Scientists in recent years have come to see the accumulation of senescent cells and associated inflammation—”inflammaging”—as a major driver of tissue aging and disease susceptibility.

The researchers confirmed the likely relevance of their mouse findings to human biology with similar findings in biopsies of livers from younger and older people.