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

将 GHR 拮抗作用与延长生命的化合物相结合：寻求协同作用

• 批准号: 10738834
• 负责人: John Joseph Kopchick
• 金额: $ 62.81万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738834
• 关键词: Acarbose; Acromegaly; Affect; Age; Aging; Animal Model; Autopsy; B-Lymphocytes; Binding; Caenorhabditis elegans; Cattle; Cell Aging; Cells; Clinical; Combined Modality Therapy; Complex; Consensus; Dasatinib; Data; Development; Diabetes Mellitus; Disease; Economic Burden; Elderly; Estradiol; Exhibits; Exposure to; FDA approved; FRAP1 gene; Female; Fibrosis; Future; Goals; Growth Hormone Receptor; Growth and Development function; Health; Healthcare Systems; Human; Hyperinsulinism; Individual; Injections; Insulin-Like Growth Factor I; Intervention; Knockout Mice; Laboratories; Laboratory mice; Life; Link; Longevity; Malignant Neoplasms; Measures; Metformin; Methods; Molecular; Mus; Mutation; Nutraceutical; Obesity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological; Predisposition; Process; Production; Quercetin; Receptor Gene; Research; Role; Serum; Sirolimus; Somavert; Testing; Therapeutic; Time; Transgenic Mice; Work; age related; antagonist; anti aging; blood glucose regulation; clinical application; cognitive function; cohort; drug candidate; end of life; frailty; healthspan; healthy aging; improved; innovation; insulin sensitivity; male; novel; pegvisomant; pharmacologic; prepuberty; prevent; renal damage; senescence; sex; synergism

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.

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 并造成巨大的经济负担。因此，找到预防、推迟甚至是 迫切需要逆转与年龄相关的表型。因为老龄化是一个复杂的、多因素的过程，目标是 可能同时需要多个途径来最佳地减缓衰老过程和防止衰老- 相关疾病。为此，最近在动物模型中的研究表明，不止一个 与单一疗法相比，基因疗法确实可以在更大程度上提高健康和寿命。在基础上建设 这一概念，我们提议的研究将利用几种有希望延长生命的联合疗法 所有这些化合物都将与生长激素受体拮抗剂(GHRA)结合进行评估。 Ghra是这项提议的主要焦点，原因有几个：i)大量证据表明 生长激素活动的减少与延缓衰老有关；ii)生长激素活动的中断被发现延长寿命 在实验室小鼠中使用的时间比任何其他方法都长；iii)药物对GH/IGF-1轴的抑制 在最近的一份共识声明中，被确定为六种最有希望减缓衰老的干预措施中的第一种 老龄化专家；IV)最近的数据显示，雌性小鼠的中位和最长寿命增加， Ghra(Somvert，聚乙二醇化Ghra)是FDA批准的唯一针对GH的药物 作用，并已被证明是安全和有效的人类；和vi)GHR拮抗尚未 单独或与其他牙科治疗剂联合进行老化研究的适当评估，尽管其 作为一种治疗癌症的药物有着明确的前景。因此，我们假设，将GHR对抗与其他 延长生命的化合物将在更大程度上改善健康和长寿，而不是这些单独的疗法 独自一人。在目标1中，我们首次寻求测试涉及GHR拮抗的新的联合疗法。在……里面 目标2，我们试图理解这些新的组合所发生的机械性变化。耐人寻味的 生长激素在改变与年龄相关的B细胞中的作用--以前没有被认为与生长激素作用有关，而是 最近被认为在与衰老相关的病理中很重要的-也将被评估。我们的长期目标 是开发新的、基于机制的治疗方法来减缓人类的衰老过程。 在这项提案中，使用现有营养食品和FDA批准的药物的可行临床组合将 被放在首位。因为这些化合物中的每一种都有其独特的局限性(即，表现出温和的 单独改善，影响不同的衰老途径，可以是性别特有的)，它们的组合应该 同时针对多个与衰老相关的途径，以最大限度地提高健康和寿命。

项目成果

Mice with gene alterations in the GH and IGF family.

• DOI: 10.1007/s11102-021-01191-y
• 发表时间: 2022-03
• 期刊: Pituitary
• 影响因子: 3.8
• 作者: Qian Y;Berryman DE;Basu R;List EO;Okada S;Young JA;Jensen EA;Bell SRC;Kulkarni P;Duran-Ortiz S;Mora-Criollo P;Mathes SC;Brittain AL;Buchman M;Davis E;Funk KR;Bogart J;Ibarra D;Mendez-Gibson I;Slyby J;Terry J;Kopchick JJ
• 通讯作者: Kopchick JJ

Cholinergic neurons in the hypothalamus and dorsal motor nucleus of the vagus are directly responsive to growth hormone.

• DOI: 10.1016/j.lfs.2020.118229
• 发表时间: 2020-10-15
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Quaresma PGF;Teixeira PDS;Wasinski F;Campos AMP;List EO;Kopchick JJ;Donato J Jr
• 通讯作者: Donato J Jr

Could calgranulins and advanced glycated end products potentiate acromegaly pathophysiology?

钙颗粒蛋白和高级糖化终产物能否增强肢端肥大症的病理生理学？

• DOI: 10.1016/j.ghir.2019.04.002
• 发表时间: 2019
• 期刊: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
• 作者: Kruse,ColinPS;Cottrill,DavidA;Kopchick,JohnJ
• 通讯作者: Kopchick,JohnJ

Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons.

禁食和长期食物限制对 GH 分泌的影响不同，与 AgRP 神经元中 GH 受体信号传导无关。

• DOI: 10.1111/jne.13254
• 发表时间: 2023
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: deSousa,MariaE;Gusmao,DanielaO;DosSantos,WillianO;Moriya,HenriqueT;deLima,FelipeF;List,EdwardO;Kopchick,JohnJ;DonatoJr,Jose
• 通讯作者: DonatoJr,Jose

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

• DOI: 10.3390/cancers12123640
• 发表时间: 2020-12-04
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Qian Y;Basu R;Mathes SC;Arnett NA;Duran-Ortiz S;Funk KR;Brittain AL;Kulkarni P;Terry JC;Davis E;Singerman JT;Henry BE;List EO;Berryman DE;Kopchick JJ
• 通讯作者: Kopchick JJ