Aging reduces liver resiliency by dysregulating Hedgehog signaling

Area of Science:

• Hepatology
• Aging Biology
• Molecular Signaling

Background:

• Older age is a significant risk factor for liver damage, impairing regeneration and resilience.
• The mechanisms underlying age-related decline in liver function are not fully understood.
• Hedgehog signaling plays a role in liver metabolic homeostasis and regeneration.

Purpose of the Study:

• To investigate the hypothesis that Hedgehog signaling is dysregulated in aging hepatocytes.
• To determine if impaired Hedgehog signaling contributes to reduced liver resiliency and regeneration in aged individuals.
• To explore the molecular consequences of Hedgehog pathway disruption in aging liver.

Main Methods:

• Partial hepatectomy (PH) was performed on young and old wild-type mice.
• Conditional deletion of Smoothened (Smo) in hepatocytes of young mice to disrupt Hedgehog signaling.
• RNA sequencing and Gene Ontology analysis to assess pathway changes and cellular responses.
• Correlation of signaling changes with liver regenerative capacity and cellular markers of aging.

Main Results:

• Old hepatocytes exhibited reduced proliferation and downregulated Hedgehog signaling post-PH.
• Hedgehog pathway inhibition in young hepatocytes mimicked age-related regenerative deficits.
• Dysregulated Hedgehog signaling was associated with activated innate immune responses and suppressed growth pathways.
• Hedgehog inhibition promoted telomere shortening and mitochondrial dysfunction in hepatocytes.

Conclusions:

• Hedgehog signaling is dysregulated and downregulated in aging hepatocytes.
• This dysregulation impairs liver regeneration and enhances vulnerability to damage.
• Restoring Hedgehog signaling may be a therapeutic strategy to improve liver health in aging individuals.