Growth Hormone Receptor Antagonism Extends Lifespan.

Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan(definition). Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. This drug was based on our laboratory's early 1990s discovery that mutating a codon for a conserved glycine-at position 119 in bovine GH or 120 in human GH-to a variety of amino acids, including lysine, ultimately converted GH from an agonist to antagonist. Since Pegvisomant has poor affinity to rodent GHR, it has not been tested for its ability to extend lifespan in rodents. To address this gap, we evaluated survival in GHA transgenic mice, a mouse line that played a crucial role in the discovery and development of Pegvisomant and has been maintained in our lab since 1991. While a prior study with several limitations failed to detect lifespan extension in GHA mice, our current study addressing these limitations shows that both median and maximal lifespan were significantly increased in male (p = 0.044; p = 0.0037) and female GHA mice (p = 2 × 10^-8; p = 9 × 10^-6), with maximal lifespan extended by 186 and 265 days, respectively. Analysis of an independent cohort of 2-year-old mice revealed that GHA males and females were less frail with enhanced grip strength despite increased adiposity. These findings demonstrate for the first time that GH antagonism can improve health and extend lifespan.