Isolating the direct effects of growth hormone on lifespan and metabolism in mice

Prior studies have shown that interrupting the growth hormone/insulin‐like growth factor‐I (GH/IGF‐I) signaling axis extends laboratory mouse lifespan, but confounding effects of additional gene or hormone deficiencies that exist in commonly used models of GH/IGF‐I interruption obscure the specific effect of GH on longevity. We address this issue by using mice with a specific knockout of the GH gene and show that both males and females on a mixed genetic background display extended lifespans resulting from GH deficiency. Our physiological assessment of these mice revealed that in addition to weighing significantly less and displaying significantly greater body fat (as a percentage of body weight), GH deficient mice display significant impairments in glucose metabolism and preferential fat utilization. These data provide strong evidence that GH deficiency is directly responsible for the altered nutrient utilization and extended lifespan that is commonly observed in mouse models of GH/IGF‐I interruption. Previous studies suggest that disrupting the growth hormone (GH) pathway can extend mouse lifespan, but confounding factors often cloud this relationship. To clarify, we used mice with a specific GH gene knockout and found that both males and females had extended lifespans solely due to GH deficiency. Physiological assessments showed these mice were lighter, had higher body fat percentages, and exhibited impaired glucose metabolism. Our results strongly indicate that GH deficiency directly impacts nutrient utilization and contributes to increased lifespan.