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

描述（由申请人提供）：雷帕霉素是唯一明确显示可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，有很大的需要和机会来了解雷帕霉素是如何工作的-无论是为了开发安全有效的治疗方法，还是为了深入了解衰老本身的基本机制。雷帕霉素的典型靶点是mTORC 1，这是一种营养感应激酶，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，mTORC 1靶点S6激酶1（S6 K1）的消融模拟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，据推测雷帕霉素通过抑制哺乳动物中的mTORC 1/S6 K1轴来模拟CR。 然而，与CR形成鲜明对比的是，雷帕霉素实际上导致胰岛素抵抗，并且至少在细胞中抑制线粒体的产生和活性。 这些是令人惊讶的和潜在的非常重要的观察结果，因为胰岛素敏化和线粒体生物合成增加都被认为有助于CR诱导的寿命。 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mTORC 2的结果，此外，特异性抑制mTORC 1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合成和活性的抑制是否也发生在体内。 如果是这样的话，雷帕霉素将使我们能够提供第一个明确的证据，证明线粒体的生物合成可以与长寿分开。 在第二线实验中，我们将用雷帕霉素治疗S6 K1基因敲除小鼠，以检验S6 K1独立机制有助于其对寿命的影响的假设。 有若干理由相信情况将会如此。 S6 K1消融在生理学上产生非常不同的变化，并且不会延长男性的生命，而雷帕霉素则可以。 此外，mTORC 2同源物调节蠕虫的寿命，因此我们证明雷帕霉素破坏小鼠中的mTORC 2为S6 K1独立效应提供了候选机制。 最后，我们将探讨mTORC 2中断的组织特异性后果。 肝脏中mTORC 2的缺失似乎介导了雷帕霉素对胰岛素敏感性的不利影响，改善这些影响可能会导致补充方法来提高药物的安全性和有效性。 另一方面，另一种胰岛素信号分子IRS 2在大脑中的丢失先前已被证明可以延长寿命，因此神经元mTORC 2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年龄相关疾病进展并延长小鼠最长生存时间的机制将为促进健康的人类衰老提供重要的见解和可能的新治疗靶点。

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.