Senescent Cells Disrupt Liver Zonation and Metabolic Identity with Age
A mouse study mapped senescence patterns across liver zones at different ages and found that aged livers lose normal zonation. Distinct age-, zone-, and sex-related senescence signatures were associated with changes in zone markers, and accelerated-senescence models supported a causal role. Senescent hepatocytes showed a strong inflammatory secretion profile and altered WNT and BMP signaling.
In mice, researchers combined spatial transcriptomics with single-nucleus RNA sequencing to compare livers across ages. By 18 months, the usual division of labor between liver regions had blurred: zone 2 markers spread while zone 3 markers fell, suggesting hepatocytes were losing specialized identity.
Older animals also showed senescence patterns that varied by age, liver region, and sex, and these tracked with zonation changes. Ercc1-mutant mice with faster senescence reproduced the pattern, strengthening causal evidence. A no-zone hepatocyte-like group grew with age and had the strongest inflammatory secretory signal; senescent hepatocytes showed lower WNT and higher BMP signaling.
Because the work is in mice, its near-term societal impact may be indirect. It could sharpen how researchers think about liver aging and age-related metabolic vulnerability, potentially informing future biomarker or treatment research. Older adults, especially those with declining liver function or metabolic disease, may eventually benefit if such findings translate; clinicians and drug developers may also use the zonation framework to interpret liver injury and aging. Any health or economic effects would depend on replication and clinical translation.