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

Ben-Avraham, DannyGovindaraju, Diddahally R.Budagov, TemuriFradin, DelphineDurda, PeterLiu, BingOtt, SandyGutman, DanielleSharvit, LitalKaplan, RobertBougnères, PierreReiner, AlexShuldiner, Alan R.Cohen, PinchasBarzilai, NirAtzmon, Gil2017-07-242017Ben-Avraham, D., D. R. Govindaraju, T. Budagov, D. Fradin, P. Durda, B. Liu, S. Ott, et al. 2017. “The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.” Science Advances 3 (6): e1602025. doi:10.1126/sciadv.1602025. http://dx.doi.org/10.1126/sciadv.1602025.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33490934Although 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.en-USSciAdv r-articlesGeneticsgrowth hormone receptorIGF-Ipositive pleiotropylongevityCentenariansd3-GHRThe GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller statureJournal Article2017-07-2410.1126/sciadv.1602025