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

 描述(申请人提供)：雷帕霉素(MTOR)信号通路的机制靶点已被确认为无脊椎动物模型和小鼠长寿的重要和进化保守的决定因素。雷帕霉素是一种mTOR信号转导的小分子抑制剂，已被证明是第一个能够延长小鼠寿命并在临床前小鼠模型中延缓或消除几种与年龄相关的疾病的药物。尽管这些研究激起了人们的兴奋，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，阐明mTOR信号在人类衰老中的作用是具有挑战性的，而且评估其对人类寿命的影响表面上是不可能的。我们认为，在非人类灵长类动物模型中，通过测试mTOR的抑制是否延长寿命，可以朝着弥合这一关于翻译潜力的知识鸿沟迈出重要的一步。在老龄化研究方面，常见的绒猴(Callithrix Jacchus)为其他常用的非人类灵长类动物提供了许多优势，其中最重要的是它们的正常寿命是所有类人灵长类动物中最短的，并且可以在单一R01赠款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慢性抑制绒猴的mTOR信号。我们发现，雷帕霉素治疗健康绒猴对所有受试者都有良好的耐受性，在体内抑制mTOR信号转导，并且不会增加罹患 与其临床使用有关的许多影响。因此，我们的实验室首次在非人类灵长类动物中验证了抑制mTOR既能延长寿命又能改善健康的假设。在目标1中，我们直接评估了慢性mTOR抑制对恒河猴寿命和病理的影响。因为寿命是衡量衰老影响的“黄金标准”，如果是肯定的，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抑制对恒河猴健康衰老功能标记物的长期影响。老龄化研究的首要目标是确定促进健康衰老的方法，在不改善或保持健康的情况下延长寿命可能被视为有害的。我们通过针对雷帕霉素影响小鼠的五个生理系统的微创测试的纵向评估来确定功能：肌肉、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mTOR抑制在绒猴中的作用。自噬是蛋白质和细胞器在细胞中降解的一种细胞过程，是mTOR信号的重要目标，但这一过程在灵长类动物寿命中的作用在很大程度上尚不清楚。总体而言，我们的长期 目的是确定抑制mTOR是否促进灵长类动物的健康衰老，为以mTOR为基础的治疗奠定基础，以改善人类的健康。

 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.