Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.
Molecular and Cellular Biology program, Ohio University, Athens, Ohio, USA.
Aging Cell. 2021 Dec;20(12):e13506. doi: 10.1111/acel.13506. Epub 2021 Nov 22.
Studies in multiple species indicate that reducing growth hormone (GH) action enhances healthy lifespan. In fact, GH receptor knockout (GHRKO) mice hold the Methuselah prize for the world's longest-lived laboratory mouse. We previously demonstrated that GHR ablation starting at puberty (1.5 months), improved insulin sensitivity and female lifespan but results in markedly reduced body size. In this study, we investigated the effects of GHR disruption in mature-adult mice at 6 months old (6mGHRKO). These mice exhibited GH resistance (reduced IGF-1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects.
多项物种研究表明，减少生长激素（GH）的作用可以延长健康寿命。事实上，生长激素受体敲除（GHRKO）小鼠是世界上寿命最长的实验室小鼠。我们之前的研究表明，从青春期（1.5 个月）开始，GHR 缺失可改善胰岛素敏感性和雌性寿命，但会导致显著的体型减小。在这项研究中，我们研究了成熟成年小鼠（6 个月大）中 GHR 破坏的影响（6mGHRKO）。这些老鼠表现出 GH 抵抗（IGF-1 减少和 GH 血清水平升高）、身体肥胖增加、瘦体重减少，对体长的影响最小。重要的是，6mGHRKO 雄性具有增强的胰岛素敏感性和减少的肿瘤，而雌性表现出延长的中位和最大寿命。此外，与雄性相比，雌性的空腹血糖和氧化损伤降低，而不论 Ghr 是否缺失。总的来说，成年小鼠中 GH 作用的破坏导致了性别二态性影响，这表明老年时减少 GH 可能具有治疗效果。
