Modulating Growth Hormone Action as a Target for Improved Health and Longevity

摘要 本实验室先前培育了生长激素受体基因破坏小鼠（GHR-/-）， 生长激素（GH）的生理重要性。在由此产生的众多发现中， 老鼠线，也许是最不寻常的，是他们被公认为最长寿的实验室 老鼠.许多研究表明，这些小鼠也改善了长期健康状况，因为它们是 对认知能力下降、衰老细胞积累、糖尿病和癌症的抵抗力。人类与 GHR基因的突变（Laron综合征）也可以预防糖尿病和癌症，这表明， GHR-/-小鼠的研究具有临床意义。因此，我们实验室的长期目标是 确定这些非凡的健康和长寿的分子机制， 效益本申请的总体目标是确定是否干扰GH作用 “暂时”复制了在GHR-/-小鼠中发现的健康益处，如果将两种单独的延长寿命的方法结合起来， 干预措施比单独采取任何一种干预措施都能更大程度地延长寿命。完成这些 目的：（1）确定是否干扰幼年（2周龄）或成年（4周龄）的GHR 月）小鼠改善健康和寿命，和（2）确定雷帕霉素治疗GHR-/-或艾姆斯 老鼠可以改善健康，进一步延长寿命。我们的假设是， 在GHR-/-小鼠中观察到的延长的寿命可以通过出生后施加的干预来复制， 在与机制不完全重叠的干预措施相结合时，情况得到进一步改善。我们 初步数据与最近发表的数据相结合表明：（1）GHR的时间中断， 6周龄是可行的，并且导致雌性的最大寿命增加;（2）GHR-/-小鼠具有组织 呼吸和线粒体功能的特定改变，可能会影响其有利的葡萄糖 （3）雷帕霉素和GHR-/-对葡萄糖代谢和葡萄糖代谢都有相反的作用。 GH/IGF-1轴，这表明结合这些干预措施可以增加寿命， 协同地。我们的方法是创新的，因为它结合了操纵基因的方法， 表达来控制GH/IGF-1轴（即出生后或成年后选择性地破坏GHR基因）（目的 1)以及GH缺乏或抗性与雷帕霉素的结合（目的2）。我们还将评估寿命 以及这些新小鼠中与衰老相关的多种机制，包括GH/IGF-1的成分， 轴、葡萄糖稳态、mTOR活性、细胞衰老和能量代谢指数（细胞 呼吸、线粒体功能、代谢灵活性）。拟议的研究是重要的，因为它将 提供了一个更好地了解生长激素在衰老中的作用，并将揭示有效的策略和线索， 改善健康的干预措施。

Abstract Our laboratory previously generated the growth hormone receptor gene disrupted mouse (GHR-/-) to study the physiological importance of growth hormone (GH). Of the many discoveries that have resulted from this mouse line, perhaps the most extraordinary, is that they are recognized as the longest-lived laboratory mouse. Numerous studies indicate that these mice also have improved long-term health as they are resistance to cognitive decline, accumulation of senescent cells, diabetes, and cancer. Humans with mutations in the GHR gene (Laron Syndrome) are also protected from diabetes and cancer, indicating that studies with GHR-/- mice have clinical relevance. Therefore, the long-term goal of our laboratory is to determine the molecular mechanisms that are responsible for these remarkable health and longevity benefits. The overall objectives in this application are to determine whether disrupting GH action “temporally” replicates the health benefits found in GHR-/- mice and if combining two separate life-extending interventions can increase lifespan to a greater extent than either intervention alone. To accomplish these objectives, we propose two Specific Aims: (1) to determine if disrupting GHR in young (2 week) or adult (4 month) mice improves health and longevity, and (2) to determine if rapamycin treatment of GHR-/- or Ames mice can improve health and further extend lifespan. Our hypotheses are that the health benefits and extended longevity seen in GHR-/- mice can be replicated by interventions applied after birth and may be further improved when combined with interventions whose mechanisms are not fully overlapping. Our preliminary data combined with recently published data demonstrate that: (1) Temporal disruption of GHR at 6 weeks of age is feasible and results in increased maximal lifespan in females; (2) GHR-/- mice have tissue specific alterations in respiration and mitochondrial function that could influence their favorable glucose metabolism; and (3) Rapamycin and GHR-/- have opposite effects on both glucose metabolism and the GH/IGF-1 axis, suggesting that combining these interventions may enhance lifespan additively or synergistically. Our approach is innovative in that it combines methodologies for manipulating gene expression to control the GH/IGF-1 axis (i.e. GHR gene disruption selectively after birth or in adulthood)(Aim 1) and for combining of GH deficiency or resistance with rapamycin (Aim 2). We will also evaluate longevity and multiple mechanisms associated with aging in these novel mice including components of the GH/IGF-1 axis, glucose homeostasis, mTOR activity, cellular senescence, and indices of energy metabolism (cellular respiration, mitochondrial function, metabolic flexibility). The proposed research is significant as it will provide a better understanding of the role of GH in aging and will reveal clues for effective strategies and interventions that improve health.