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

雷帕霉素对健康和长寿影响的分子机制。

• 批准号: 8852520
• 负责人: Joseph A. Baur
• 金额: $ 40.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852520
• 关键词: Ablation; Adverse effects; Affect; Aging; Animals; Biogenesis; Brain; Caloric Restriction; Cells; Complex; Cultured Cells; Data; Deterioration; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Female; Food; Gender; Generations; Growth; Health; Health Promotion; Hepatic; Homologous Gene; Human; IRS2 gene; Immunosuppression; In Vitro; Individual; Insulin; Insulin Resistance; Intervention; Knockout Mice; Lead; Life; Light; Liver; Longevity; Lower Organism; Mammals; Measures; Mediating; Metabolism; Metformin; Mitochondria; Molecular; Mus; Neurons; Organelles; Pharmaceutical Preparations; Phosphotransferases; Physiology; Production; Protein Biosynthesis; Reactive Oxygen Species; Resveratrol; Ribosomal Protein S6 Kinase; Risk; Risk Factors; Safety; Science; Signal Transduction; Signaling Molecule; Sirolimus; Societies; Source; Stress; Testing; Therapeutic; Time; Tissues; Work; age related; anti aging; cardiovascular disorder risk; cardiovascular risk factor; combat; design; detection of nutrient; drug efficacy; grasp; improved; in vivo; insight; insulin sensitivity; insulin signaling; mTOR protein; male; neuron loss; neurotensin mimic 1; new therapeutic target; prevent; research study; respiratory

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.

描述（由申请人提供）：雷帕霉素是唯一已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，我们非常需要和有机会了解雷帕霉素的作用原理——既可以开发安全有效的治疗方法，也可以深入了解衰老本身的基本机制。雷帕霉素的典型靶标是 mTORC1，这是一种营养感应激酶，其同源物与低等生物体中热量限制 (CR) 延长寿命有关。 在小鼠中，mTORC1 靶标 S6 激酶 1 (S6K1) 的消融模拟了 CR 的显着特征，包括胰岛素敏感性、线粒体生物发生和寿命的增加。 因此，推测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，并且至少在细胞中抑制线粒体的产生和活性。 鉴于胰岛素敏化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。 我们最近表明，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，我们计划测试细胞中观察到的线粒体生物发生和活性的抑制是否也发生在体内。 如果是这样，雷帕霉素将使我们首次清楚地证明线粒体生物发生可以与长寿脱钩。 在第二个实验中，我们将用雷帕霉素治疗 S6K1 敲除小鼠，以检验 S6K1 独立机制有助于其延长寿命的假设。 有很多理由相信情况会如此。 S6K1 消融会产生截然不同的生理变化，并且不会延长男性的寿命，而雷帕霉素却可以。 此外，mTORC2 同源物调节线虫的寿命，因此我们证明雷帕霉素会破坏小鼠中的 mTORC2，因此为不依赖于 S6K1 的效应提供了候选机制。 最后，我们将探讨 mTORC2 破坏的组织特异性后果。 肝脏中 mTORC2 的缺失似乎会介导雷帕霉素对胰岛素敏感性的不利影响，而改善这些影响可能会导致采取补充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 的缺失此前已被证明可以延长寿命，因此神经元 mTORC2 的缺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与年龄相关的疾病的进展并延长小鼠的最大生存时间的机制将为促进人类健康衰老提供重要的见解，并可能提供新的治疗靶点。