Abstract

Objective Global growth hormone receptor knockout (GHR −/− ) extends lifespan but also causes adverse effects. As a key target of growth hormone (GH), adipose tissue may mediate aging, though the underlying mechanisms remain unclear. We investigated how adipose-specific GHR ablation influences multisystem aging, with a focus on metabolic health and cognitive function. Methods We generated adipose-specific GHR knockout (Ad-GHRKO) mice and assessed healthspan parameters including cognitive function, musculoskeletal integrity and metabolic profiles. Adipose tissue remodelling and inflammation were examined by histology and protein analysis. Subcutaneous white adipose transcriptomics identified gene expression changes. The role of the AMPK-SIRT1-Ac-PPARγ pathway in metabolic elasticity and aging was elucidated by Western blot and in vitro assays. Results Ad-GHRKO mice exhibited extended healthspan, with enhanced cognitive performance, improved muscle strength and bone mass and a lifespan increase trend. Mechanistically, GHR ablation remodelled adipose tissue, reducing age-related lipid redistribution, restoring glucose homeostasis and creating a low-inflammation, high-plasticity depot. This reprogramming boosted systemic metabolic elasticity primarily via AMPK-SIRT1-Ac-PPARγ activation. AMPK inhibition abolished benefits, confirming its pivotal role. Conclusion Our findings identify adipose-specific GH signalling antagonism as a regulatory switch that recalibrates the local balance between GH and IGF-1 actions, thereby reprogramming adipose tissue to promote coordinated systemin metabolic resilience during aging. This tissue-targeted strategy circumvents the developmental and endocrine limitations associated with global GH/IGF-1 suppression. Rather than merely extending lifespan, adipose-specific GHR ablation supports healthier aging by preserving metabolic homeostasis, maintaining multisystem functional integrity and reducing age-associated inflammatory and fibrotic r