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

Danny Ben-Avraham, Diddahally R. Govindaraju, Temuri Budagov, Delphine Fradin, Peter Durda, Bing Liu, Sandy Ott, Danielle Gutman, Lital Sharvit, Robert C. Kaplan, Pierre Bougnères, Alex Reiner, Alan R. Shuldiner, Pinchas Cohen, Nir Barzilai, Gil Atzmon

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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.

Original languageEnglish (US)
Article numbere1602025
JournalScience advances
Volume3
Issue number6
DOIs
StatePublished - Jun 1 2017

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Somatotropin Receptors
Growth Hormone
Exons
Somatomedins
Amish
Lymphocytes
Genes
Homozygote
Genetic Polymorphisms
Sex Characteristics
Phosphotransferases
Multivariate Analysis
Alleles
Genotype
Regression Analysis
Health
Growth
Serum

ASJC Scopus subject areas

  • Medicine(all)

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The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. / Ben-Avraham, Danny; Govindaraju, Diddahally R.; Budagov, Temuri; Fradin, Delphine; Durda, Peter; Liu, Bing; Ott, Sandy; Gutman, Danielle; Sharvit, Lital; Kaplan, Robert C.; Bougnères, Pierre; Reiner, Alex; Shuldiner, Alan R.; Cohen, Pinchas; Barzilai, Nir; Atzmon, Gil.

In: Science advances, Vol. 3, No. 6, e1602025, 01.06.2017.

Research output: Contribution to journalArticle

Ben-Avraham, D, Govindaraju, DR, Budagov, T, Fradin, D, Durda, P, Liu, B, Ott, S, Gutman, D, Sharvit, L, Kaplan, RC, Bougnères, P, Reiner, A, Shuldiner, AR, Cohen, P, Barzilai, N & Atzmon, G 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, vol. 3, no. 6, e1602025. https://doi.org/10.1126/sciadv.1602025
Ben-Avraham, Danny ; Govindaraju, Diddahally R. ; Budagov, Temuri ; Fradin, Delphine ; Durda, Peter ; Liu, Bing ; Ott, Sandy ; Gutman, Danielle ; Sharvit, Lital ; Kaplan, Robert C. ; Bougnères, Pierre ; Reiner, Alex ; Shuldiner, Alan R. ; Cohen, Pinchas ; Barzilai, Nir ; Atzmon, Gil. / The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. In: Science advances. 2017 ; Vol. 3, No. 6.
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AU - Fradin, Delphine

AU - Durda, Peter

AU - Liu, Bing

AU - Ott, Sandy

AU - Gutman, Danielle

AU - Sharvit, Lital

AU - Kaplan, Robert C.

AU - Bougnères, Pierre

AU - Reiner, Alex

AU - Shuldiner, Alan R.

AU - Cohen, Pinchas

AU - Barzilai, Nir

AU - Atzmon, Gil

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N2 - 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.

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