William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
Department of Medicine, University of Wisconsin-Madison.
J Gerontol A Biol Sci Med Sci. 2020 Jan 1;75(1):14-23. doi: 10.1093/gerona/glz056.
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.
mTORC1（雷帕霉素靶蛋白复合物 1）的抑制作用通过药物雷帕霉素延长了包括啮齿动物在内的模型生物的寿命和健康寿命，现在有证据表明，雷帕霉素及其类似物也可能对狗和人类具有恢复活力的作用。然而，长期雷帕霉素治疗相关的副作用，其中许多是由于抑制第二个 mTOR 复合物 mTORC2 引起的，这似乎排除了将雷帕霉素常规用作治疗与年龄相关疾病的疗法。在这里，我们讨论了最近的发现，这些发现表明，实现雷帕霉素的抗衰老作用可能不需要强烈、慢性地抑制两个 mTOR 复合物。相反，通过各种新兴技术适度但特异性地抑制 mTORC1，包括雷帕霉素衍生物的间歇性或短暂治疗，或特定的饮食方案，可能足以在减少副作用的情况下促进健康和长寿。我们还将讨论开发新分子的前景，这些新分子通过利用过去十年中对 mTORC1 信号的详细分子理解，将为选择性抑制 mTORC1 提供新途径。我们的结论是，基于 mTORC1 选择性抑制的疗法可能很快就能更安全地治疗衰老疾病。
