Deleting liver growth hormone receptors accelerates aging phenotypes and shortens lifespan in mice

In a study of mice, researchers found that deleting the growth hormone receptor specifically in hepatocytes accelerated aging-related decline. The genetically modified mice showed shortened lifespans, increased cellular senescence, cognitive decline, reduced bone mineralization, and worse inflammaging. They also showed impaired resilience to metabolic stress. Loss of liver growth hormone receptors raised circulating growth hormone levels, driving adipose tissue lipolysis and CD36-dependent liver fat accumulation. This deficiency worsened liver pathologies in both naturally aged mice and mice fed a high-fat diet. Mechanistically, hepatic receptor loss impaired STAT5b phosphorylation and elevated PPARγ expression, which upregulated Pdk4 and Cd36 transcription to trigger mitochondrial damage and lipid buildup. Pharmacologically inhibiting PDK4 in vivo alleviated these age-related pathologies.