Growth hormone receptor gene disruption in mature‐adult mice improves male insulin sensitivity and extends female lifespan

Abstract

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Transient early life growth hormone exposure permanently alters brain, muscle, liver, macrophage, and adipocyte status in long‐lived Ames dwarf mice

“…However, studies involving deletion of the gene at 6 weeks or 6 months of age indicate that GH signaling during adult life has a role in determination of longevity in female mice. 34,35 Interestingly, in these studies longevity of males was not affected by disrupting GH signaling during adult life.…”

Musculoskeletal Effects of Altered GH Action

“…Furthermore, reduced skeletal growth in GHRKO mice has been associated with premature growth plate closure and reduced chondrocyte proliferation, bone turnover and periosteal bone apposition ( Sims et al, 2000 ). To study the effects of reduced GH action postnatally, a mouse line with disrupted GHR at 6 months of age (6mGHRKO) was recently reported ( Duran-Ortiz et al, 2021b ; Dixit et al, 2021 ). Disrupting GHR globally at an adult age results in more slender bones, expansion of the marrow cavity, reduced osteocyte lacunar number, and increases in lacunar volume and loss of canalicular connectivity ( Dixit et al, 2021 ).…”

“…GHRKO mice have decreased body length and weight, increased insulin sensitivity, and markedly increased lifespan ( Coschigano et al, 2003 ). As for GHD, mice with congenital GH deficiency (GH knockout or −/− mice) ( List et al, 2019 ) and mice with adult GHD via GHR disruption starting at 6 months of age (6mGHRKO) ( Duran-Ortiz et al, 2021b ) or induced somatotroph destruction ( Luque et al, 2011 ; Cordoba-Chacon et al, 2014 ; Poudel et al, 2021 ) have recently been developed. Many other mouse lines have also been created that provide insight into GH’s action although they lack clinical correlates.…”

Chasing Methuselah: adult inducible GHRKO mice

“…In fact, the current record holder for the Methuselah Mouse Prize for Longevity – a mouse that lived one week shy of five years – is the GHR “knockout” (GHRKO) mouse [ 1 ]. A new study by our laboratory suggests that partial knockdown of the GHR beginning at 6 months of age can also extend median and maximal lifespan in female mice [ 2 ].…”

“…Despite these promising results, GHR gene disruption later in life would have greater clinical relevance since interventions initiated at more advanced ages minimize the duration of pharmacological administration without disturbing growth or development. To address this, we conducted a second study recently published [ 2 ]. GHR disruption was initiated at 6 months of age – a mature adult age in mice – as opposed to 1.5m in the initial study.…”