Adipose‐Specific GHR Deletion Attenuates Brain Aging and Cognitive Decline in Aged Mice

Brain aging is marked by neuronal loss, synaptic deterioration, neuroinflammation, and proteinopathies, all of which contribute to cognitive decline. Although systemic suppression of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling has been shown to extend lifespan and enhance cognitive function, the specific role of GH signaling in adipose tissue during brain aging remains unclear. In this study, we used aged (18-24 months) adipose-specific GH receptor knockout (Ad-GHRKO) mice and their littermate controls to investigate this relationship. We found that deletion of GHR in adipose tissue significantly attenuated key features of brain aging. Aged Ad-GHRKO mice exhibited reduced neuronal loss in the cortex and hippocampus, diminished neuroinflammation, decreased cellular senescence, and lower levels of tau phosphorylation in the hippocampus compared to controls. Additionally, synaptic integrity, indicated by hippocampal PSD95 expression, and cortical neuronal excitability were preserved. Importantly, Ad-GHRKO mice showed improved cognitive performance across multiple domains, including recognition memory (novel object recognition, NOR), working memory (Y-maze), spatial learning/memory (Morris water maze), and associative fear memory (passive avoidance). These findings suggest adipose GH signaling as a previously unrecognized peripheral regulator of brain aging and cognition, implicating adipose GHR as a therapeutic target for mitigating age-related cognitive decline.