Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.
Geroscience. 2023 Oct;45(5):2769-2783. doi: 10.1007/s11357-023-00935-x. Epub 2023 Oct 6.
Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
雷帕霉素（mTORC1 蛋白激酶的抑制剂）的治疗已在多种模型系统中反复证明能延长寿命并预防或延缓与年龄相关的疾病。由于担心雷帕霉素及其类似物在人类中可能存在严重副作用的风险，包括免疫抑制和代谢紊乱，这谨慎地限制了其作为治疗与衰老相关疾病的应用。在过去的十年中，我们和其他研究人员已经开发出一个可行的模型，表明虽然抑制 mTORC1 能促进健康衰老，但雷帕霉素的许多负面副作用与“脱靶”抑制第二种 mTOR 复合物 mTORC2 有关。雷帕霉素抑制 mTORC1 和 mTORC2 的动力学和分子机制的差异表明，可以通过间歇性给药方案或其他可能更选择性抑制 mTORC1 的雷帕霉素类似物来利用雷帕霉素的治疗窗口。然而，这种干预在人类中的最佳给药方案和长期疗效尚不清楚。在这里，我们强调了正在进行或即将进行的临床试验，这些试验将解决关于雷帕霉素和雷帕霉素类似物在几个临床相关结局上的安全性、药代动力学、药效学和疗效的悬而未决的问题。这些早期阶段研究的结果将有助于指导 3 期临床试验的设计，以确定雷帕霉素是否可以安全地用于抑制 mTORC1 以治疗和预防人类与年龄相关的疾病。
