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Roles of Growth Hormone-Dependent JAK-STAT5 and Lyn Kinase Signaling in Determining Lifespan and Cancer Incidence

Yash Chhabra1,2,3, Helle Bielefeldt-Ohmann4, Tania Louise Brooks1

  • 1Institute for Molecular Bioscience, University of Queensland, St Lucia 4069, Australia.

Endocrinology
|October 8, 2024
PubMed

Insights

Growth hormone receptor (GHR) signaling impacts longevity. Disrupting janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) pathways extends lifespan, while LYN kinase activation plays a key role in this longevity.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Gerontology

Background:

  • Loss of growth hormone (GH) or its receptor is linked to extended lifespan in rodents.
  • Understanding the specific signaling pathways mediating GH receptor (GHR)-induced longevity is crucial for aging research.

Purpose of the Study:

  • To investigate the role of distinct GHR signaling pathways (JAK2-STAT and LYN-ERK1/2) in determining lifespan and cancer incidence.
  • To elucidate the molecular mechanisms underlying GHR-mediated longevity by analyzing gene and protein expression in mutant mice.

Main Methods:

  • Generated GHR-mutant mice with deletions in key signaling pathways: STAT5 response, JAK2 activation (Box1 mutation), and complete receptor knockout.
  • Assessed lifespan, performed histopathological analysis to determine causes of death, and analyzed hepatic gene and protein expression in each mutant cohort.

Main Results:

  • The Box1-mutant males, retaining LYN activation, exhibited a significantly extended median lifespan (1016 days) compared to GHR knockout males (890 days).
  • In females, GHR Box1 knockout mice had a longer median lifespan (970 days) than GHR knockout females (911 days).
  • Removal of sexually dimorphic GHR-STAT5 signaling extended female lifespan to 1003 days from 734 days in wild-type females, indicating its repressive role in longevity.

Conclusions:

  • GHR signaling pathways exhibit a complex interplay, with JAK2-STAT pathways generally repressive for longevity, while LYN kinase activation promotes extended lifespan.
  • GHR-STAT5 signaling regulates genes involved in insulin sensitivity, oxidative stress, and mitochondrial function.
  • LYN-responsive genes are associated with DNA repair, cell cycle control, and anti-inflammatory responses, highlighting a yin-yang relationship between JAK2 and LYN in lifespan determination.
Keywords:
GH receptor mutantsinflammationinsulin sensitivitylongevityoxidative stresssexual dimorphism

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