Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution.

Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model. Midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling. Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.