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 P.; Shuldiner, Alan R.; Cohen, Pinchas; Barzilai, Nir; Atzmon, Gil

doi:10.1126/sciadv.1602025

Cited by 52 publications

(52 citation statements)

References 53 publications

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“…S7 ). This replicated findings from a previous, locus-specific study that found an association with height in a different cohort ( 6 ) . That same study also suggested sex-specificity of the effect of GHRd3 on longevity, so the UK Biobank dataset was examined further to test if GHRd3 is correlated with any phenotypic effects in a sex-specific manner.…”

supporting

confidence: 89%

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

Resendez¹,

Saitou²,

Parisi

et al. 2019

Preprint

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The deletion of the third exon of the growth hormone receptor ( GHRd3 ) is one of the most common genomic structural variants in the human genome. This deletion has been linked to response to growth hormone, placenta size, birth weight, growth after birth, time of menarche, adult height, and longevity. However, its evolutionary history and the exact mechanisms through which it affects phenotypes remain unresolved. While the analysis of thousands of genomes suggests that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals, it underwent a paradoxical adaptive reduction in frequency approximately 30 thousand years ago, a demographic signature that roughly corresponds with the emergence of multiple modern human behaviors and a concurrent population expansion. Using a mouse line engineered to contain the deletion, pleiotropic and sex-specific effects on organismal growth, the expression levels of hundreds of genes, and serum lipid composition were documented, potentially involving the nutrient-dependent mTORC1 pathway. These growth and metabolic effects are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability. The last distinctive prehistoric shift in allele frequency might be related to newly developed technological buffers against the effects of oscillating resource levels.

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supporting

confidence: 89%

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

Resendez¹,

Saitou²,

Parisi

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…A recent report of exceptional longevity in males associated with enrichment of an exon-3-deleted isoform of the GHR (d3-GHR) provides a new perspective of GHR isoforms and lifespan extension (228). An in-frame splicing of exon-2 to the exon-4 of GHR results in d3-GHR splice variant, with 22 amino acids less at the N-terminal than the full-length GHR.…”

Section: Lifespan In D3-ghr Variantsmentioning

confidence: 99%

“…Individuals with d3-GHR have low serum IGF-1and IGFBP1 levels yet surprisingly reduced levels of GH, GHR and GH binding protein (GHBP). The d3-GHR male offspring of centenarians were relatively tall and, remarkably, had a significantly increased lifespan (228) indicating augmented GH-GHR signaling (228). It is worth inquiring whether a reduced activity of metalloprotease TACE/ADAM17 action or regulators of it like TIMP3 (229,230) in cleaving the GHbound extracellular domain of the GHR homodimer generating GHBP is a causal link; or if there is a modified kinetics of interaction of the GH molecule with a 22-amino acid deleted extracellular domain of the d3-GH giving rise to a GHBP analog.…”

Section: Lifespan In D3-ghr Variantsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.

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“…In addition, mice heterozygous for IGF1R knockout live 26% longer than the wild type mice [3]. Genetic polymorphism studies have identified genetic variations that are associated with extreme human longevity in centenarians, including FOXO3A [71], IGF1R [72], and GHR [73], suggesting that the IIS pathway may influence health and longevity in humans.…”

Section: Insulin/igf-1 Signalingmentioning

confidence: 99%

Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species

Tian

Seluanov

Gorbunova

2017

Trends in Endocrinology & Metabolism

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Aging is a global decline of physiological functions, leading to an increased susceptibility to diseases and ultimately death. Maximum lifespans differ up to 200-fold between mammalian species. Although considerable progress has been achieved in identifying conserved pathways that regulate individual lifespan within model organisms, whether the same pathways are responsible for the interspecies differences in longevity remains to be determined. Recent cross-species studies have begun to identify pathways responsible for interspecies differences in lifespan. Here, we review the evidence supporting the role of anti-cancer mechanisms, DNA repair machinery, insulin/IGF1 signaling, and proteostasis in defining species lifespans. Understanding the mechanisms responsible for the dramatic differences in lifespan between species will have a transformative effect on developing interventions to improve human health and longevity.

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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

Abstract: The d3-GHR genetic variant polymorphism modulates GH responsiveness throughout life span and positively affects male longevity.

Cited by 52 publications

References 53 publications

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species

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