In rodents, loss of GH or its receptor is associated with extended lifespan. We aimed to determine the signalling process resulting in this longevity using GH receptor (GHR) mutant mice with key signalling pathways deleted and correlate this with cancer incidence and expression of genes associated with longevity. GHR uses both canonical JAK2-STAT signalling as well as signalling via LYN-ERK1/2 pathway. We utilised C57BL/6 mice with loss of key receptor tyrosines and truncation resulting in (1) loss of most STAT5 response to GH or (2) total inability to generate STAT5 to GH or (3) loss of Box1 to prevent activation of JAK2 but not LYN kinase or (4) total knockout of the receptor. For each mutant we analysed lifespan, histopathology to determine likely cause of death, and hepatic gene and protein expression. The extended lifespan is evident in the Box1 mutant males (retains Lyn activation) have median lifespan of 1016 days compared to 890 days for the Ghr-/- males. In the females, GhrBox1-/- mice have a median lifespan of 970 days compared to 911 days for the knockout females. Sexually dimorphic GHR-STAT5 is repressive for longevity, since its removal results in a median lifespan of 1003 days in females compared to 734 days for wild type females. Numerous transcripts related to insulin sensitivity, oxidative stress response and mitochondrial function are regulated by GHR-STAT5, however LYN responsive genes involve DNA repair, cell cycle control, and anti-inflammatory response. There appears to be a yin-yang relationship between JAK2 and LYN that determines lifespan.