Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction

ABSTRACT

Aging drives physiological decline and predisposes individuals to multiple age‐related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age‐related diseases remains incompletely defined. Here, we demonstrate that hepatocyte‐specific GHR knockout mice display accelerated aging‐related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte‐specific GHR ablation mediates adipose‐liver crosstalk that promotes adipose lipolysis and CD36‐dependent hepatic steatosis. Hepatocyte‐specific GHR deficiency also promotes liver aging and aggravates age‐related hepatic pathologies in both naturally aged and high‐fat diet (HFD)‐fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPARγ expression. Enhanced nuclear translocation of PPARγ activates transcription of Pdk4 and Cd36 , leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self‐amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in vivo effectively ameliorates the age‐related pathologies induced by hepatocyte‐specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age‐related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age‐related liver disorders.