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Single-nuclei profiling of aged liver tissue from mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE280513 | GEO | 2025/07/16

REPOSITORIES: GEO

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Project description:Older age is a major risk factor for damage to many tissues, including liver. Aging undermines resiliency (i.e., the ability to recover from injury) and impairs liver regeneration. The mechanisms whereby aging reduces resiliency are poorly understood. Hedgehog is a signaling pathway with critical mitogenic and morphogenic functions during development. Recent studies indicate that Hedgehog regulates metabolic homeostasis in adult liver. The present study evaluates the hypothesis that Hedgehog signaling becomes dysregulated in hepatocytes during aging, resulting in decreased resiliency and therefore, impaired regeneration and enhanced vulnerability to damage. Methods: Partial hepatectomy (PH) was performed on young and old wild type mice and Smoothened (Smo)-floxed mice treated with AAV8-TBG luciferase (control) or AAV8-TBG-Cre vectors to conditionally delete Smo and disrupt Hedgehog signaling specifically in hepatocytes. Changes in signaling were correlated with changes in regenerative responses and compared among groups. Results: Old livers had fewer hepatocytes proliferating after PH. RNA sequencing identified Hedgehog as a top down-regulated pathway in old hepatocytes before and after the regenerative challenge. Deleting Smo in healthy young hepatocytes before PH prevented Hedgehog pathway activation after PH and inhibited regeneration. GO analysis demonstrated that both old and Smo-deleted young hepatocytes had activation of pathways involved in innate immune responses and suppression of several signaling pathways that control liver growth and metabolism including insulin-like growth factor, Wnt and NOTCH. Hedgehog inhibition promoted telomere shortening and mitochondrial dysfunction in hepatocytes, consequences of aging that promote inflammation and impair tissue growth and metabolic homeostasis. Conclusion: Hedgehog signaling is dysregulated in old hepatocytes. This accelerates aging, resulting in decreased resiliency and therefore, impaired liver regeneration and enhanced vulnerability to damage.

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Single-nuclei profiling of aged liver tissue from mice

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