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 Kaplan; Pierre Bougnères; Alex Reiner; Alan R. Shuldiner; Pinchas Cohen; Nir Barzilai; Gil Atzmon

doi:10.1126/sciadv.1602025

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 Kaplan, Pierre Bougnères, Alex Reiner, Alan R. Shuldiner, Pinchas Cohen, Nir Barzilai, Gil Atzmon

Department of Human Biology

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	e1602025
Journal	Science advances
Volume	3
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.1602025
State	Published - Jun 2017

Bibliographical note

Funding Information:
We thank all the participants from the three cohorts used in this study. This study was funded in part by grants from the NIH [(P01AG021654 to N.B.), (1R01AG042188 to G.A.), and (1R01AG 034430 and 1P01AG034906 to P.C.)], the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072 to N.B.), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation Grant to N.B. and P.C.), and Diabetes Center (DK-20541 to N.B.). D.F. and P.B. were supported by INSERM with additional contribution from Association de Recherche sur le Diabète and an institutional grant from Novo Nordisk France. CHS was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, and N01-HC-45133; grant number U01 HL080295 from the National Heart, Lung, and Blood Institute; U19 AG023122 from the National Institute on Aging Longevity Consortium; and P30 AG021334 from the National Institute on Aging, Claude D. Pepper Older Americans Independence Centers; and grant R01 HL-071862 (to A.R.), with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://chs-nhlbi.org. Genotyping services for CHS were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract number N01-HG-65403).

Publisher Copyright:
Copyright © 2017 The Authors, some rights reserved.

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10.1126/sciadv.1602025

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Ben-Avraham, D., Govindaraju, D. R., Budagov, T., Fradin, D., Durda, P., Liu, B., Ott, S., Gutman, D., Sharvit, L., Kaplan, R., Bougnères, P., Reiner, A., Shuldiner, A. R., 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, 3(6), Article e1602025. https://doi.org/10.1126/sciadv.1602025

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

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.",

author = "Danny Ben-Avraham and Govindaraju, {Diddahally R.} and Temuri Budagov and Delphine Fradin and Peter Durda and Bing Liu and Sandy Ott and Danielle Gutman and Lital Sharvit and Robert Kaplan and Pierre Bougn{\`e}res and Alex Reiner and Shuldiner, {Alan R.} and Pinchas Cohen and Nir Barzilai and Gil Atzmon",

note = "Funding Information: We thank all the participants from the three cohorts used in this study. This study was funded in part by grants from the NIH [(P01AG021654 to N.B.), (1R01AG042188 to G.A.), and (1R01AG 034430 and 1P01AG034906 to P.C.)], the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072 to N.B.), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation Grant to N.B. and P.C.), and Diabetes Center (DK-20541 to N.B.). D.F. and P.B. were supported by INSERM with additional contribution from Association de Recherche sur le Diab{\`e}te and an institutional grant from Novo Nordisk France. CHS was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, and N01-HC-45133; grant number U01 HL080295 from the National Heart, Lung, and Blood Institute; U19 AG023122 from the National Institute on Aging Longevity Consortium; and P30 AG021334 from the National Institute on Aging, Claude D. Pepper Older Americans Independence Centers; and grant R01 HL-071862 (to A.R.), with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://chs-nhlbi.org. Genotyping services for CHS were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract number N01-HG-65403). Publisher Copyright: Copyright {\textcopyright} 2017 The Authors, some rights reserved.",

year = "2017",

month = jun,

doi = "10.1126/sciadv.1602025",

language = "English",

volume = "3",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "6",

}

Ben-Avraham, D, Govindaraju, DR, Budagov, T, Fradin, D, Durda, P, Liu, B, Ott, S, Gutman, D, Sharvit, L, Kaplan, R, 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

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T1 - The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

AU - Ben-Avraham, Danny

AU - Govindaraju, Diddahally R.

AU - Budagov, Temuri

AU - Fradin, Delphine

AU - Durda, Peter

AU - Liu, Bing

AU - Ott, Sandy

AU - Gutman, Danielle

AU - Sharvit, Lital

AU - Kaplan, Robert

AU - Bougnères, Pierre

AU - Reiner, Alex

AU - Shuldiner, Alan R.

AU - Cohen, Pinchas

AU - Barzilai, Nir

AU - Atzmon, Gil

N1 - Funding Information: We thank all the participants from the three cohorts used in this study. This study was funded in part by grants from the NIH [(P01AG021654 to N.B.), (1R01AG042188 to G.A.), and (1R01AG 034430 and 1P01AG034906 to P.C.)], the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072 to N.B.), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation Grant to N.B. and P.C.), and Diabetes Center (DK-20541 to N.B.). D.F. and P.B. were supported by INSERM with additional contribution from Association de Recherche sur le Diabète and an institutional grant from Novo Nordisk France. CHS was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, and N01-HC-45133; grant number U01 HL080295 from the National Heart, Lung, and Blood Institute; U19 AG023122 from the National Institute on Aging Longevity Consortium; and P30 AG021334 from the National Institute on Aging, Claude D. Pepper Older Americans Independence Centers; and grant R01 HL-071862 (to A.R.), with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://chs-nhlbi.org. Genotyping services for CHS were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract number N01-HG-65403). Publisher Copyright: Copyright © 2017 The Authors, some rights reserved.

PY - 2017/6

Y1 - 2017/6

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.

AB - 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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VL - 3

JO - Science advances

JF - Science advances

IS - 6

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ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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