MON-051 - Mid-Life Growth Hormone Receptor Inhibition Extends Lifespan and Healthspan through Hepatocyte Reprogramming

Attenuation of growth hormone (GH) signaling is one of the most robust interventions known to extend lifespan and healthspan across species. Notably, the longest-lived laboratory mouse on record results from congenital disruption of the GH receptor (GHR) resulting in profound GH insensitivity and protection against diabetes, cancer, and age-related functional decline. These results are similar to those found in Laron Syndrome individuals. However, lifelong GH suppression limits normal growth, precluding direct clinical translation. We therefore hypothesized that targeted inhibition of GH action initiated in adulthood could preserve normal development while promoting healthy aging.
To test this, we developed a series of inducible mouse models enabling adult-onset GHR ablation. Building on prior work demonstrating that GHR disruption at 1.5 and 6 months of age partially recapitulates the benefits of congenital GH resistance, we ablated GHR signaling in middle-aged (12-month-old) mice, hereafter referred to as 12mGHRKO mice. Remarkably, 12mGHRKO mice exhibit significant lifespan extension in both sexes. Male 12mGHRKO mice show improved insulin sensitivity, reduced fasting glucose, enhanced healthspan measures, and improved bone health compared to age-matched controls. These benefits occur despite increased adiposity, underscoring a dissociation between obesity and functional decline in the context of reduced GH action.
At the molecular level, markers of cellular senescence (p16INK4a and p21) are reduced in liver and adipose tissue in a sex-specific manner. Single-nucleus RNA sequencing reveals feminization of hepatocyte gene expression in males, accompanied by upregulation of xenobiotic metabolism and detoxification pathways, consistent with a hepatoprotective transcriptional reprogramming associated with improved metabolic resilience. Ongoing pathology studies are evaluating cancer incidence to further define end-of-life disease burden.
Collectively, these findings demonstrate that mid-life disruption of GH signaling is sufficient to extend lifespan and improve functional aging outcomes while preserving normal growth and physical performance. Importantly, because a GH receptor antagonist is already FDA-approved, this work establishes a strong preclinical and translational framework for late-life, mechanism-based interventions targeting GH signaling to delay age-associated disease and functional decline in humans.
Acknowledgements: This work is supported by the State of Ohio's Eminent Scholar Program, by NIH grant AG059779, by the Glenn/AFAR Postdoctoral fellowship in Aging Research, by Nathan Shock Centers (University of Southern California/Buck Institute and UT Health San Antonio), and by the Diabetes Institute and by the AMVETS.

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