The role of mTOR inhibition on longevity and healthy aging in a non-human primate

mTOR 抑制对非人类灵长类动物寿命和健康衰老的作用

• 批准号: 9282387
• 负责人: Adam Salmon
• 金额: $ 54.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282387
• 关键词: 10 year old; Address; Adult; Adverse effects; Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Atherosclerosis; Autophagocytosis; Biological Assay; Brain; Callithrix; Callithrix jacchus jacchus; Cardiac; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Data; Disease; Disease model; FRAP1 gene; Female; Foundations; Funding; Genetic; Goals; Gold; Grant; Haplorhini; Health; Health Benefit; Human; Inflammation; Invertebrates; Knowledge; Laboratories; Lesion; Life; Long-Term Effects; Longevity; Malignant Neoplasms; Mammals; Measures; Mediating; Mission; Modeling; Monitor; Monkeys; Mus; Muscle; Organ; Organelles; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiological; Play; Positioning Attribute; Primates; Process; Proteins; Regulation; Research; Risk; Role; Series; Signal Pathway; Signal Transduction; Sirolimus; South American; System; Testing; Time; Tissue Sample; Tissues; Translations; United States National Institutes of Health; age related; base; cohort; end of life; functional decline; glucose metabolism; healthy aging; improved; in vivo; innovation; insight; male; minimally invasive; mortality; mouse model; nonhuman primate; novel; pre-clinical; prevent; public health relevance; small molecule inhibitor; standard measure; tool; translational approach

 DESCRIPTION (provided by applicant): The mechanistic target of rapamycin (mTOR) signaling pathway has been identified as an important and evolutionary conserved determinant of longevity in invertebrate models and mice. Rapamycin, a small molecule inhibitor of mTOR signaling, has been demonstrated as the first pharmaceutical capable of extending longevity in mice and also delaying or abrogating several age-related diseases in pre-clinical mouse models. Despite the excitement raised by these studies, their potential translational relevance in terms of preventing age-related disease in humans remains unclear. Clarifying the role of mTOR signaling in human aging is challenging for several reasons and assessing its effect on human longevity is ostensibly impossible. We propose that a major step towards bridging this knowledge gap regarding translation potential can be made by testing whether inhibition of mTOR extends longevity in a non-human primate model. In the context of aging studies, the common marmoset (Callithrix jacchus) offers many advantages other commonly utilized non- human primates, foremost of which is that their normal lifespan is the shortest of any anthropoid primate and amenable to testing effects on longevity within the funding period of a single R01 grant. In our preliminary studies, we used rapamycin as a pharmaceutical tool to chronically inhibit mTOR signaling in marmosets. We found that rapamycin treatment in healthy marmosets was well-tolerated by all subjects, inhibited mTOR signaling in vivo, and did not increase risk for many effects that have been associated with its use clinically. Thus, our laboratory is in the unique position to test for the first time the hypothesis that inhibition of mTOR will both extend lifespan and improve healthspan in a non-human primate. In aim 1, we directly assess the effect of chronic mTOR inhibition on both lifespan and pathology in marmosets. Because longevity is the "gold-standard" for measuring effects on aging, if positive, the results from this aim will provide the most conclusive evidence that inhibition of mTOR can slow aging in primates. In aim 2, we test the long-term effects of mTOR inhibition on functional markers of healthy aging in the marmoset. An overarching goal of aging research is to define means to promote healthy aging, and extension of lifespan without improving or maintaining health could be viewed as detrimental. We determine function using longitudinal assessments of minimally-invasive assays targeting five physiological systems shown to be affected by rapamycin in mice: muscle, brain, cardiac, glucose metabolism and inflammation. In aim 3, we define what role autophagy plays in mediating the effects of mTOR inhibition in marmosets. While autophagy, a cellular process by which proteins and organelles are degraded in the cell, is an important target of mTOR signaling, the role of this process in primate longevity is largely unknown. Overall, our long-term goal is to determine whether inhibiting mTOR promotes healthy aging in primates to build the foundation for targeting mTOR-based therapies to improve health in humans.

 描述（由申请人提供）：雷帕霉素（mTOR）信号通路的机制靶点已被确定为无脊椎动物模型和小鼠寿命的重要且进化保守的决定因素。雷帕霉素是一种mTOR信号传导的小分子抑制剂，已被证明是第一种能够延长小鼠寿命的药物，也是临床前小鼠模型中延迟或消除几种年龄相关疾病的药物。尽管这些研究令人兴奋，但它们在预防人类年龄相关疾病方面的潜在翻译相关性仍不清楚。由于几个原因，澄清mTOR信号在人类衰老中的作用具有挑战性，并且评估其对人类寿命的影响表面上是不可能的。我们建议，通过测试抑制mTOR是否会延长非人灵长类动物模型的寿命，可以迈出弥合关于翻译潜力的知识差距的重要一步。在衰老研究的背景下，普通绒猴（Callithrix jacchus）提供了许多其他常用的非人灵长类动物的优势，其中最重要的是它们的正常寿命是任何灵长类动物中最短的，并且适合在单个R01资助的资助期内测试对寿命的影响。在我们的初步研究中，我们使用雷帕霉素作为药物工具来长期抑制绒猴中的mTOR信号传导。我们发现，雷帕霉素治疗在健康绒猴中所有受试者都耐受良好，抑制体内mTOR信号传导，并且不会增加风险。 许多与其临床使用相关的影响。因此，我们的实验室处于独特的位置，首次测试了抑制mTOR将延长非人类灵长类动物的寿命并改善其健康状况的假设。在目标1中，我们直接评估慢性mTOR抑制对绒猴寿命和病理学的影响。因为寿命是衡量衰老影响的“金标准”，如果是阳性的，这一目标的结果将提供最确凿的证据，证明抑制mTOR可以减缓灵长类动物的衰老。在目标2中，我们测试了mTOR抑制对绒猴健康衰老的功能标志物的长期影响。老龄化研究的首要目标是确定促进健康老龄化的方法，延长寿命而不改善或保持健康可能被视为有害。我们使用针对五个生理系统的微创检测的纵向评估来确定功能，这些生理系统在小鼠中被雷帕霉素影响：肌肉，大脑，心脏，葡萄糖代谢和炎症。在目标3中，我们定义了自噬在介导绒猴中mTOR抑制的作用中起什么作用。虽然自噬是细胞中蛋白质和细胞器降解的细胞过程，是mTOR信号传导的重要靶点，但该过程在灵长类动物寿命中的作用在很大程度上尚不清楚。总的来说，我们的长期 目的是确定抑制mTOR是否能促进灵长类动物的健康衰老，为靶向基于mTOR的疗法改善人类健康奠定基础。