The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.
Level 4 - case-series / case-control
Cross-sectional multi-cohort genetic association study combined with in vitro laboratory experiments.
PubMed 28630896 · doi:10.1126/sciadv.1602025
What was done
Researchers evaluated the association between growth hormone receptor exon 3 deletion (d3-GHR) homozygosity and longevity across four independent cohorts totaling 841 participants: the Longevity Genes Project (LGP, n = 567), Old Order Amish (n = 152), Cardiovascular Health Study (n = 61), and French Long-Lived Study (n = 61). They performed cross-sectional trend analyses with age, a male-specific mega-analysis, and phenotypic comparisons of height and serum IGF-1. Transformed lymphocytes from LGP participants were tested in vitro for cell growth and extracellular signal-regulated kinase (ERK) activation following growth hormone (GH) exposure.
What was found
The prevalence of d3-GHR homozygosity increased linearly with age in the LGP (8% increase; P = 0.01), Amish (16% increase; P = 0.02), and French (23.5% increase; P = 0.02) cohorts, but was not statistically significant in the Cardiovascular Health Study cohort (14.2% increase; P = 0.14). A mega-analysis of males across all cohorts demonstrated a 26% increase in prevalence with age (P = 0.007). LGP d3/d3 homozygotes averaged 1 inch taller than wild-type carriers (P = 0.05) and had lower serum IGF-1 levels (P = 0.003). Multivariate regression estimated that the d3/d3 genotype adds approximately 10 years to lifespan. Transformed d3/d3 lymphocytes showed greater growth and ERK activation in response to GH versus wild-type cells (P < 0.01).
Why it matters
This study links a common genetic polymorphism conferring enhanced GH sensitivity to extended lifespan and greater height in human males, presenting a contrast to animal models where reduced GH signaling extends life span.
Limits
The study relies on observational cross-sectional comparisons of survivors rather than longitudinal lifetime tracking. Two of the four cohorts had very small sample sizes (n = 61 each), the height difference reached borderline statistical significance (P = 0.05), and in vitro mechanistic validation was limited to transformed lymphocyte cell lines.
Cited by
- supports Genetic polymorphisms in the IGF-1 receptor and FOXO genes are associated with human longevity.