Single-nuclei profiling of aged liver tissue from mice

The liver undergoes a slower aging process compared to other organs owing to its unique regenerative ability. Mammalian liver aging commonly manifests as impaired metabolic performance, reduced organ volume and blood/bile flow, altered cellular and organelle composition, and delayed regenerative ability after toxic insults. Although aging-induced degenerative changes in liver structure and function are not necessarily pathologic, these are associated with an increased risk and susceptibility to chronic liver diseases. However, little is known about the molecular mechanisms driving the morphological changes and functional decline of the aging liver. For an unbiased characterization of aging-driven changes in major cell types of the liver, we employed single-nucleus RNA sequencing (snRNA-seq). A total of 41,568 nuclei isolated from young and aged livers reflected the expected cell diversity of the liver. Analysis of the snRNA-seq dataset revealed that aged livers had altered percentages of hepatocytes across all zones and that aged hepatocytes were associated with zone-specific alterations in expression of gen­es involved in aging, senescence, and inflammation.