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）：雷帕霉素是唯一明确证明可以延长小鼠寿命的唯一化合物。 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人类药物的效用。 因此，有很大的需求和机会来了解雷帕霉素的工作原理 - 既是为了开发安全有效的治疗剂，又要深入了解衰老本身的基本机制。雷帕霉素的规范靶标是MTORC1，它是一种营养感应激酶，其同源物已与低生物体中热量限制（CR）延长寿命。 在小鼠中，MTORC1靶标S6激酶1（S6K1）CR的显着特征的消融，包括胰岛素敏感性的提高，线粒体生物发生和寿命。 因此，已经假定雷帕霉素通过抑制哺乳动物中的mTORC1/s6k1轴来模仿Cr。 然而，与CR形成鲜明对比，雷帕霉素实际上会引起胰岛素抵抗，至少在细胞中抑制了线粒体的产生和活性。 考虑到胰岛素敏化和线粒体生物发生的增加，这些观察结果令人惊讶且可能非常重要，这是有助于CR诱导的寿命的。 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标MTORC2的结果，此外，MTORC1的特定抑制会延长寿命，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基因的抑制和活性也发生在体内。 如果是这样，雷帕霉素将使我们能够首次明确的证明线粒体生物发生可以与寿命脱在一起。 在第二行实验中，我们将用雷帕霉素处理S6K1基因敲除小鼠，以检验以下假设：S6K1无关机制有助于其对寿命的影响。 有很多原因认为情况。 S6K1消融在生理学上产生截然不同的变化，并且不会延长雄性的生命，而雷帕霉素则可以。 此外，MTORC2同源物调节蠕虫中的寿命，我们的证明是雷帕霉素破坏小鼠中的MTORC2，为S6K1无关效应提供了一种候选机制。 最后，我们将探索MTORC2破坏的组织特异性后果。 肝脏中MTORC2的丧失似乎介导了雷帕霉素对胰岛素敏感性的有害作用，并改善这些作用可能会导致互补的方法来提高药物的安全性和功效。 另一方面，以前已显示出大脑中另一个胰岛素信号分子IRS2的丧失可以延长寿命，因此神经元MTORC2的丧失可能有助于雷帕霉素对寿命的有益作用。 阐明雷帕霉素能够预防或减慢与年龄相关疾病的进展并延长小鼠的最大生存时间的机制将提供重要的见解，并可能提供新的治疗靶标，以促进健康的人类衰老。