Combining GHR antagonism with life extending compounds: a search for synergies

摘要 人类老龄化和无数与年龄相关的疾病是我们医疗保健面临的最大挑战之一 造成了巨大的经济负担。因此，找到预防、推迟甚至 迫切需要逆转与年龄相关的表型。由于衰老是一个复杂的多因素过程， 可能需要同时使用多种途径来最佳地减缓衰老过程并防止衰老- 相关疾病。为此，最近在动物模型中的研究表明， 与单一疗法相比，吉尔福确实能在更大程度上增进健康和延长寿命。基础上 根据这一概念，我们提出的研究将利用联合疗法，包括几种有前途的延长寿命的方法。 所有这些化合物都将与生长激素受体拮抗剂（GHRA）组合进行评价。 GHRA是本提案的主要重点，原因如下： GH作用的减少与衰老减缓有关; ii）GH作用的中断被发现延长寿命 在实验室小鼠中的时间比任何其他方法都长; iii）GH/IGF-1轴的药物抑制已经被证明是有效的。 在最近的一份共识声明中， 老龄化专家; iv）最近的数据显示，雌性小鼠的中位寿命和最长寿命增加， GHRA; v）GHRA（Somavert，聚乙二醇化GHRA）是唯一FDA批准的专门针对GH的药物 作用，并已被证明是安全和有效的人类;和vi）GHR拮抗作用尚未被证实。 单独或与其他促衰老剂联合使用， 明确承诺作为一种生发药。因此，我们假设将GHR拮抗作用与其他 延长寿命的化合物将在更大程度上改善健康和长寿，而不是这些单独的治疗方法 一个人在目标1中，我们试图首次测试涉及GHR拮抗作用的新型联合疗法。在 目的2，我们试图了解这些新组合发生的机械变化。一个耐人寻味 生长激素在改变年龄相关的B细胞中的作用-以前没有与生长激素作用有关， 最近被认为在衰老相关的病理学中很重要-也将进行评估。我们的长期目标 是开发新的，基于机制的治疗方法，用于减缓人类的衰老过程。 在这项提案中，采用现有营养保健品和FDA批准的药物的可行临床组合将 被优先考虑。由于这些化合物中的每一种都有其独特的局限性（即，显示轻度 单独的改善，影响不同的衰老途径，可以是性别特异性的），它们的组合应该 同时针对多种与衰老相关的途径，以最大限度地提高健康和长寿。

Abstract Human aging and the myriad of age-associated diseases are among the greatest challenges in our healthcare system and result in a significant economic burden. Thus, finding interventions that prevent, postpone, or even reverse age-related phenotypes are urgently needed. As aging is a complex, multifactorial process, targeting multiple pathways simultaneously are likely needed to optimally slow the aging process and prevent age- related disease. To this end, recent studies in animal models now indicate that combination of more than one gerotherapeutic can indeed enhance health and lifespan to a greater extent than monotherapies. Building on this concept, our proposed studies will utilize combination therapies involving several promising life-extending compounds all of which will be evaluated in combination with the growth hormone receptor antagonist (GHRA). GHRA is the primary focus of this proposal for several reasons: i) a strong body of evidence shows that reduction in GH action is associated with slowed aging; ii) disruption of GH action was found to extend lifespan in laboratory mice longer than any other method; iii) pharmaceutical inhibition of the GH/IGF-1 axis has been identified as the first of six most promising interventions to slow aging in a recent consensus statement of aging experts; iv) recent data show increases in median and maximal lifespan in female mice expressing GHRA; v) GHRA (Somavert, pegylated GHRA) is the only FDA approved drug that specifically targets GH action and has been shown to be safe and effective in humans; and vi) GHR antagonism has not been properly evaluated for aging research alone or in combination with other gerotherapeutic agents despite its clear promise as a gerotherapeutic drug. Thus, we hypothesize that combining GHR antagonism with other life-extending compounds will improve health and longevity to a greater extent than these individual therapies alone. In Aim 1, we seek to test novel combination therapies involving GHR antagonism for the first time. In Aim 2, we seek to understand the mechanistic changes that occur with these novel combinations. An intriguing role for GH in altering age-associated B cells – which has not previously been linked to GH action and is more recently appreciated to be important in aging-related pathologies – will also be assessed. Our long-term goal is to develop novel, mechanism-based, therapeutic approaches for attenuating the aging process in humans. In this proposal, feasible clinical combinations that employ existing nutraceuticals and FDA approved drugs will be given top consideration. As each of these compounds have their own unique limitations (i.e., show mild improvements individually, influence different aging pathways, can be sex-specific), their combination should target multiple aging-associated pathways simultaneously to maximize health and longevity.