The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

Abstract

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (<i>d3-GHR</i>) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of <i>d3-GHR</i> homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; <i>P</i> = 0.01), 152 of the Old Order Amish (16% increase; <i>P</i> = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; <i>P</i> = 0.14), and 61 of the French Long-Lived Study (23.5% increase; <i>P</i> = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; <i>P</i> = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP <i>d3</i>/<i>d3</i> homozygotes were 1 inch taller than the wild-type (WT) allele carriers (<i>P</i> = 0.05) and also showed lower serum IGF-1 levels (<i>P</i> = 0.003). Multivariate regression analysis indicated that the presence of <i>d3</i>/<i>d3</i> genotype adds approximately 10 years to life span. The LGP d3/<i>d3-GHR</i> transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (<i>P</i> < 0.01), indicating a GH dose response. The <i>d3-GHR</i> variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.