Researchers find that aging-related cellular changes may weaken the liver’s organization, identity, and ability to perform essential metabolic functions.

As people age, certain cells in the body stop dividing but remain active, releasing substances that promote inflammation and disrupt the surrounding tissues. A new study suggests that these so-called senescent cells may play an important role in the aging of the liver by interfering with its normal organization and function.

The liver is divided into specialized zones, each responsible for carrying out distinct metabolic tasks. This organized structure allows liver cells, known as hepatocytes, to perform their functions efficiently. However, researchers found that this organization gradually deteriorates with age.

As part of the Cellular Senescence Network Consortium, scientists examined liver tissue from mice of different ages using advanced techniques that map gene activity and identify individual cell types. Their goal was to understand how cellular senescence affects liver aging.

Aging blurs the liver’s specialized zones

The researchers discovered that the distinct genetic signatures that define the liver’s zones became less pronounced as the mice aged. By middle age, 18 months in mice, genes normally associated with the liver’s third zone showed reduced activity, while markers associated with the second zone appeared across a broader area.

These changes suggest that liver cells gradually lose some of their specialized identities, potentially affecting how effectively they carry out their metabolic roles.

The findings also revealed that cellular senescence varied according to the animals’ age, sex, and the liver zone being examined. Importantly, the researchers observed similar patterns in genetically modified mice that experience accelerated cellular senescence, strengthening the evidence that senescent cells contribute to age-related changes in the liver.

A group of cells shows stronger signs of aging

One of the study’s notable findings was the expansion of a group of hepatocyte-like cells that no longer displayed clear characteristics of any particular liver zone.

These cells showed the strongest signs of the senescence-associated secretory phenotype (SASP)—a collection of inflammatory and other signaling molecules released by senescent cells.

Although these signals are part of the biological changes associated with cellular senescence, their continued release may disturb communication between neighboring cells and interfere with the liver’s normal functions.

The researchers also identified two signaling pathways that may help explain the loss of liver organization: reduced WNT signaling and increased bone morphogenetic protein (BMP) signaling. Changes in these pathways may contribute to the breakdown of the genetic programs that maintain liver cell identity and zonation.

Understanding the biology of liver aging

Senescent cells tend to accumulate as the body ages, potentially in part because the immune system becomes less efficient at removing them. Once these cells stop dividing, they can remain in tissues and release substances that contribute to chronic inflammation and changes in tissue structure.

The new findings provide evidence that these cells may affect more than inflammation alone. They may also disrupt the signals that help liver cells maintain their specialized roles.

By linking cellular senescence to the loss of liver zonation and cell identity, the study offers new insights into the biological processes underlying liver aging, even in the absence of an established liver disease.

Further research will be needed to determine whether targeting senescent cells or restoring the signaling pathways involved could help preserve liver function as organisms grow older.

Aging may gradually disrupt the liver’s carefully organized cellular system, and senescent cells could be an important part of the process. Understanding how these cells alter communication and metabolic function may help researchers identify future strategies to protect liver health with age.