02593nas a2200325   4500008004100000022001400041245014800055210006900203260001300272300001300285490000600298520161100304100002301915700003101938700002001969700002101989700001702010700001402027700001502041700002102056700001902077700001902096700002302115700001702138700002302155700001902178700001802197700001602215856003602231       2017                        eng d  a2375-254800aThe GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.0 aGH receptor exon 3 deletion is a marker of malespecific exceptio  c2017 Jun  ae16020250 v33 a<p>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.</p>1 aBen-Avraham, Danny1 aGovindaraju, Diddahally, R1 aBudagov, Temuri1 aFradin, Delphine1 aDurda, Peter1 aLiu, Bing1 aOtt, Sandy1 aGutman, Danielle1 aSharvit, Lital1 aKaplan, Robert1 aBougnères, Pierre1 aReiner, Alex1 aShuldiner, Alan, R1 aCohen, Pinchas1 aBarzilai, Nir1 aAtzmon, Gil  uhttps://chs-nhlbi.org/node/7552