Deleting the growth hormone receptor specifically in hepatocytes shortened lifespan in mice and produced accelerated aging features including cellular senescence, cognitive decline, impaired bone mineralization, and heightened inflammatory tone. Loss of hepatic GHR signaling reduced STAT5b phosphorylation and increased nuclear PPARγ activity, driving Pdk4 and Cd36 transcription, mitochondrial damage, and fatty liver; pharmacological PDK4 inhibition reversed much of the damage. The result distinguishes tissue-specific growth hormone signaling from systemic GH reduction, which has been associated with longer lifespan.
Key Points
- Liver-specific GHR deletion shortened lifespan and accelerated senescence in mice
- Elevated circulating GH drove adipose lipolysis and CD36-dependent hepatic steatosis
- PDK4 inhibition reversed mitochondrial dysfunction and age-related liver pathology
Longevity Analysis
Growth hormone reduction is often treated as uniformly pro-longevity, yet the same pathway silenced in one tissue produced the opposite outcome — mitochondrial failure in hepatocytes, ectopic fat accumulation, and inflammatory spillover into bone, cognition, and metabolic resilience. The liver's role in clearing lipids and coordinating hormonal feedback makes it a node where a single signaling defect propagates outward, which argues against interpreting circulating hormone levels as a standalone readout of biological age. For clinical translation, the practical target is downstream: PDK4 activity and the lipid-mitochondrial cycle it sustains, rather than blunt suppression of growth signaling.
Original published by Wiley Aging Cell, by Kangkang Yang, Yuli Jian, Fusheng Pang, Ming Ying, Qian Yang, Nian Liu, Shujing Wang, Yingjie Wu .