Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.

中文翻译：

---

通过抑制mTORC1进行下一代神经保护的策略。

用雷帕霉素药物抑制mTORC1（雷帕霉素复合物1的机械靶标）可延长包括啮齿类动物在内的模型生物的寿命和健康期，目前有证据表明雷帕霉素及其类似物也可对狗和人产生恢复作用。然而，与雷帕霉素长期治疗相关的副作用（其中许多是由于第二mTOR复合物mTORC2的抑制所致）似乎排除了雷帕霉素作为年龄相关疾病的治疗方法的常规用途。在这里，我们讨论了最近的发现，表明对mTOR复合物的强而长期的抑制可能对于实现雷帕霉素的抗神经保护作用不是必需的。而是通过各种新兴技术适度但特异性地抑制mTORC1，包括用雷帕霉素衍生物进行间歇或短暂治疗，或特定饮食方案可能足以促进健康和长寿，并减少副作用。我们还将讨论新分子的开发前景，这些分子将通过利用对近十年来开发的mTORC1信号的详细分子理解，为选择性抑制mTORC1提供新途径。我们得出的结论是，基于选择性抑制mTORC1的疗法可能很快就可以更安全地治疗衰老疾病。