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: 9145150
• 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/9145150
• 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; Data; Disease; 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; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; 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; 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（由适用提供）：雷帕霉素（MTOR）信号通路的机械靶标已被确定为无脊椎动物模型和小鼠中寿命的重要而进化保守的确定剂。雷帕霉素是MTOR信号传导的小分子抑制剂，已被证明是第一个能够延长小鼠寿命的药物，并且还延迟或消除了临时小鼠模型中的几种与年龄相关的疾病。尽管这些研究引起了人们的兴奋，但它们在预防人类与年龄相关的疾病方面的潜在翻译相关性尚不清楚。由于几个原因，阐明MTOR信号在人衰老中的作用是挑战，并且评估其对人寿命的影响表面上是不可能的。我们建议，可以通过测试抑制MTOR是否会在非人类灵长类动物模型中延长寿命，从而弥补有关翻译潜力的这一知识差距的重大步骤。在衰老研究的背景下，普通的marmoset（Callithrix jacchus）提供了许多其他常用的非人类灵长类动物的优势，其中最重要的是，它们的正常寿命是任何人类灵长类动物中最短的，并且可以在单个R01赠款的资金中对寿命的测试影响。在我们的初步研究中，我们使用雷帕霉素作为药物工具，以长期抑制摩尔摩斯糖的MTOR信号传导。我们发现，所有受试者都耐受耐受耐受性的雷帕霉素治疗，在体内抑制MTOR信号传导，并没有增加患的风险 与临床上的使用相关的许多效果。这是我们的实验室的独特地位，可以首次测试MTOR抑制作用将延长寿命并改善非人类灵长类动物的健康状况的假设。在AIM 1中，我们直接评估了慢性MTOR抑制对摩尔果中寿命和病理的影响。由于寿命是衡量对衰老影响的“金标准”，如果阳性，此目标的结果将提供最终的证据，证明抑制MTOR可以减缓主要的衰老。在AIM 2中，我们测试了MTOR抑制对Marmoset健康衰老功能标志物的长期影响。衰老研究的总体目标是定义手段来促进健康的衰老，而在不改善或维持健康的情况下延长寿命可能会被视为有害。我们使用针对五种生理系统的最小侵入性测定的纵向评估来确定功能，这些生理系统在小鼠中受到雷帕霉素的影响：肌肉，脑，心脏，心脏，葡萄糖代谢和感染。在AIM 3中，我们定义了自噬在介导MTOR抑制作用中的作用什么作用。虽然自噬是蛋白质和细胞器在细胞中降解的细胞过程，但它是mTOR信号传导的重要靶标，但该过程在灵长类动物寿命中的作用在很大程度上是未知的。总体而言，我们的长期 目标是确定抑制MTOR是否会促进初级健康衰老，从而为基于MTOR的疗法改善人类健康而建立基础。