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

Sci Adv. 2017 Jun 16;3(6):e1602025. doi: 10.1126/sciadv.1602025. eCollection 2017 Jun.

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 (d3-GHR) 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 d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.

Keywords: Centenarians; IGF-I; d3-GHR; growth hormone receptor; longevity; positive pleiotropy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Height / genetics*
  • Exons*
  • Female
  • Genetic Association Studies
  • Human Growth Hormone / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Kaplan-Meier Estimate
  • Longevity / genetics*
  • Male
  • Phenotype
  • Polymorphism, Genetic
  • Quantitative Trait, Heritable
  • Receptors, Somatotropin / genetics*
  • Sequence Deletion*

Substances

  • IGF1 protein, human
  • Receptors, Somatotropin
  • Human Growth Hormone
  • Insulin-Like Growth Factor I