Novel longevity enhancing pathways regulated by mTOR

摘要 mTOR通路的抑制剂是针对年龄相关功能障碍的最有希望的干预措施之一， 然而，迫切需要进一步确定延长寿命的作用，以促进 mTOR抑制剂。目前的建议将大大推动这一努力，为以下方面提供新的目标： 干预和新的标志物来监测个体对mTOR抑制的反应。的首要目标 这项研究计划是发展一个新的雷帕霉素下游靶点的机制理解， 以促进更安全和更有效的战略，促进健康老龄化。细胞衰老发生在 体细胞和干细胞群体，并有助于与年龄相关的功能障碍，我们的实验室已经 显示使用雷帕霉素的mTOR抑制可以防止进入衰老状态。mTOR途径 还调节多种干细胞群的衰老和多能性。的中心假设 雷帕霉素的mTOR抑制作用通过以下方式防止衰老并增强多能性： 增加lncRNA H19。这一假设的基本原理是我们观察到雷帕霉素增加了 非编码RNA（lncRNA）H19的水平。我们发现H19的水平在衰老过程中下降， 多能细胞H19在成体细胞的发育、分化和维持过程中起着重要作用 干细胞群体雷帕霉素增加H19水平，防止衰老并保持多能性。的 结果表明，响应于mTOR抑制而增加H19水平可能发挥双重作用，抑制了H19的表达。 衰老，同时增加成体干细胞群体的多能性。拟议 这项工作将提供关于延长寿命的新机制的变革性数据， 改善多种组织的晚期功能。

Abstract Inhibitors of the mTOR pathway are among the most promising interventions to target age‐related dysfunction, however, there is a critical need to further define the pro longevity effects to facilitate clinical development of mTOR inhibitors. The current proposal will significantly advance this effort providing new targets for intervention and novel markers to monitor individual responses to mTOR inhibition. The overarching goal of this research program is to develop a mechanistic understanding of novel downstream targets of rapamycin, in order to facilitate safer and more effective strategies to promote healthy aging. Cellular senescence occurs in both somatic and stem cell populations and contributes to age‐related dysfunction, and our laboratory has shown that mTOR inhibition using rapamycin, can prevent entry into the senescent state. The mTOR pathway also regulates senescence and pluripotency in a variety of stem cell populations. The central hypothesis of the application is that mTOR inhibition by rapamycin prevents senescence and enhances pluripotency by increasing the lncRNA H19 . The rationale for this hypothesis is our observation that rapamycin increases levels of the noncoding RNA (lncRNA) H19. We find that levels of H19 decrease during senescence and in pluripotent cells. H19 plays a central role during development and differentiation, and maintenance of adult stem cell populations. Rapamycin increases H19 levels, prevents senescence and maintains pluripotency. The results suggest that increasing H19 levels in response to mTOR inhibition may play a dual role, inhibiting senescence while simultaneously increasing pluripotency in adult stem cell populations. The proposed work will provide transformative data regarding a novel mechanism for lifespan extension and improvement of late‐life function in multiple tissues.