Molecular Mechanisms of Rapamycin's effects on Health and longevity.

描述（由申请人提供）：雷帕霉素是唯一被明确证明可以延长小鼠最大寿命的化合物。不幸的是，包括免疫抑制和心血管危险因素升高在内的副作用可能会限制该药物在人类中的应用。因此，了解雷帕霉素是如何起作用的，这既是为了开发安全有效的治疗方法，也是为了深入了解衰老本身的基本机制，这是非常必要和有机会的。雷帕霉素的典型靶点是mTORC1，这是一种营养敏感激酶，其同源物与低等生物通过热量限制（CR）延长寿命有关。在小鼠中，mTORC1靶S6激酶1 （S6K1）的消融模拟了CR的显著特征，包括胰岛素敏感性、线粒体生物发生和寿命的增加。因此，我们假设雷帕霉素通过抑制哺乳动物的mTORC1/S6K1轴来模拟CR。然而，与CR形成鲜明对比的是，雷帕霉素实际上会导致胰岛素抵抗，至少在细胞中，它会抑制线粒体的产生和活动。考虑到胰岛素增敏和线粒体生物发生的增加都被认为有助于cr诱导的长寿，这些观察结果令人惊讶，而且可能非常重要。我们最近发现，雷帕霉素诱导的胰岛素抵抗是抑制第二个靶点mTORC2的结果，此外，mTORC1的特异性抑制可以延长寿命，而不会对胰岛素信号传导产生不利影响。接下来，我们计划测试在细胞中观察到的线粒体生物生成和活性的抑制是否也发生在体内。如果是这样，雷帕霉素将使我们第一次清楚地证明线粒体的生物发生可以与长寿分离。在第二组实验中，我们将用雷帕霉素治疗S6K1基因敲除小鼠，以验证S6K1非依赖性机制有助于延长寿命的假设。有很多理由让我们相信这将是事实。S6K1消融会产生非常不同的生理变化，并且不会延长男性的寿命，而雷帕霉素却可以。此外，mTORC2同源物调节蠕虫的寿命，我们证明雷帕霉素在小鼠中破坏mTORC2，因此为s6k1独立效应提供了候选机制。最后，我们将探讨mTORC2断裂的组织特异性后果。肝脏中mTORC2的缺失似乎介导了雷帕霉素对胰岛素敏感性的有害影响，改善这些影响可能会导致互补的方法来提高药物的安全性和有效性。另一方面，大脑中另一种胰岛素信号分子IRS2的丢失已经被证明可以延长寿命，因此神经元mTORC2的丢失可能有助于雷帕霉素对寿命的有益影响。阐明雷帕霉素能够预防或减缓小鼠年龄相关疾病的进展并延长最大存活时间的机制，将为促进人类健康衰老提供重要见解，并可能提供新的治疗靶点。

DESCRIPTION (provided by applicant): Rapamycin is the only compound that has been unambiguously shown to extend the maximum lifespan of mice. Unfortunately, side effects including immunosuppression and the elevation of cardiovascular risk factors are likely to limit the utility of the drug in humans. Therefore, there is a great need and opportunity to understand how rapamycin works - both for the development of safe and effective therapeutics, and to gain insight into the basic mechanisms of aging itself. The canonical target of rapamycin is mTORC1, a nutrient sensing kinase whose homolog has been implicated in the extension of lifespan by caloric restriction (CR) in lower organisms. In mice, ablation of the mTORC1 target S6 kinase 1 (S6K1) mimics salient features of CR, including increases in insulin sensitivity, mitochondrial biogenesis, and lifespan. Therefore, it has been postulated that rapamycin mimics CR by inhibiting the mTORC1/S6K1 axis in mammals. In sharp contrast to CR, however, rapamycin actually causes insulin resistance and, at least in cells, inhibits oth the production and activity of mitochondria. These are surprising and potentially very important observations, given that both insulin sensitization and increased mitochondrial biogenesis have been suggested to contribute to CR-induced longevity. We recently showed that rapamycin-induced insulin resistance is the result of inhibiting a second target, mTORC2, and moreover, that specific inhibition of mTORC1 extends lifespan without detrimental effects on insulin signaling. Next, we plan to test whether the inhibition of mitochondrial biogenesi and activity that is observed in cells also occurs in vivo. If so, rapamycin will allow us to proide the first clear demonstration that mitochondrial biogenesis can be uncoupled from longevity. In a second line of experiments, we will treat S6K1 knockout mice with rapamycin to test the hypothesis that S6K1-independent mechanisms contribute to its effects on longevity. There are a number of reasons for believing that this will be the case. S6K1 ablation produces very different changes in physiology and does not extend life in males, whereas rapamycin does. Moreover, the mTORC2 homolog regulates longevity in worms, and our demonstration that rapamycin disrupts mTORC2 in mice therefore provides a candidate mechanism for S6K1-independent effects. Finally, we will explore the tissue-specific consequences of mTORC2 disruption. Loss of mTORC2 in the liver appears to mediate detrimental effects of rapamycin on insulin sensitivity, and ameliorating these effects could lead to complementary approaches to improve the safety and efficacy of the drug. On the other hand, loss of another insulin signaling molecule, IRS2, in the brain has previously been shown to extend life, and loss of neuronal mTORC2 might therefore contribute to the beneficial effect of rapamycin on lifespan. Elucidating the mechanisms by which rapamycin is able to prevent or slow progression of age-related diseases and extend the maximum survival time in mice will offer important insights, and likely new therapeutic targets, in the effort to promote healthy human aging.