Cell Non-autonomous Regulation of Aging via Neuronal TORC1

项目总结 衰老遗传学领域的进展表明，虽然按时间顺序衰老是不可避免的， 生物衰老是可塑性的，以细胞过程为靶点来促进体内平衡是另一种选择 以疾病为基础的战略，以减轻老年的健康负担。两者都是环保的 条件和保守的遗传途径强烈影响生理衰老和生物体的速度 改变他们的衰老和疾病屈从的速度，以响应外部提示。最具威力的 这方面的例子是饮食限制(DR)，即在没有营养不良的情况下减少食物摄入量，这会减缓每个人的衰老 到目前为止已经测试过的生物体，可以预防多种慢性疾病，包括癌症、心血管疾病 疾病和神经退行性变。我们的长期目标是阐明DR如何促进健康衰老 允许开发新的治疗方法来治疗与年龄相关的疾病。 多种分子机制被认为是DR的关键介质，包括靶 雷帕霉素复合体1(TORC1)和AMP激活的蛋白激酶(AMPK)，保守的营养传感器 对抗性地调节新陈代谢和衰老。然而，令人惊讶的是，AMPK和TORC1是如何以及在哪里 相互作用对系统衰老的调节作用尚不清楚。我们发现神经元AMPK对于延长寿命是必不可少的 从线虫体内的TORC1抑制。此外，通过RAGA-1(上游基因)的零突变延长寿命 TORC1激活剂)或rsks-1(哺乳动物S6K的同源物)被神经元特异性受体完全抑制。 神经细胞RAGA-1通过神经肽信号传递来阻止RAGA-1突变的寿命。此前，我们已经确定 线粒体动力学和RNA剪接在AMPK和TORC1长寿中的关键作用 分别进行了分析。我们现在证明，这些下游效应器接收由TORC1介导的神经元信号，以 调节衰老。我们的结果强调了神经元TORC1在细胞非自主调节中的新作用 代谢、RNA动态平衡和衰老，并提示中枢神经系统中的TORC1可能是 有针对性地促进健康老龄化。因此，我们的中心假设是，DR的有益影响 可能通过识别神经元TORC1调节的细胞非自主信号来概括。 本申请的目的是定义由TORC1介导的与以下相关的特定神经元信号 健康衰老，以及这些信号是如何在外周组织中被接收以调节线粒体网络的 和RNA剪接来延长寿命。

PROJECT SUMMARY Progress in the genetics of aging field has demonstrated that, while chronological aging is unavoidable, biological aging is malleable, and targeting cellular processes to promote homeostasis is an alternative strategy to disease based approaches to alleviate the health burdens of old age. Both environmental conditions and conserved genetic pathways strongly influence the rate of physiological aging and organisms alter the rate at which they age and succumb to disease in response to external cues. The most potent example of this is dietary restriction (DR), reduced food intake without malnutrition, which slows aging in every organism tested thus far and protects against multiple chronic diseases, including cancer, cardiovascular disease and neurodegeneration. Our long-term objective is to elucidate how DR promotes healthy aging to allow the development of novel therapeutics to treat age-related disease. Multiple molecular mechanisms have been implicated as critical mediators of DR, including the Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK), conserved nutrient sensors that antagonistically modulate metabolism and ageing. Surprisingly however, how and where AMPK and TORC1 interact to modulate systemic aging is unclear. We find that neuronal AMPK is essential for lifespan extension from TORC1 inhibition in C. elegans. Further, lifespan extension by null mutations in raga-1 (an upstream TORC1 activator) or rsks-1 (homologue of mammalian S6K) is fully suppressed by neuronal specific recues. Neuronal RAGA-1 abrogates raga-1 mutant longevity via neuropeptide signalling. Previously we have identified key roles for regulation of mitochondrial dynamics and RNA splicing in AMPK and TORC1 longevity respectively. We now show that these downstream effectors receive neuronal signals mediated by TORC1 to modulate aging. Our results highlight a new role for neuronal TORC1 in cell non-autonomous regulation of metabolism, RNA homeostasis and ageing, and suggest TORC1 in the central nervous system might be targeted to promote healthy ageing. Our central hypothesis is therefore that the beneficial effects of DR may be recapitulated via identification of cell nonautonomous signals regulated by neuronal TORC1. The objective of this application is to define the specific neuronal signals mediated by TORC1 that pertain to healthy aging, and how these signals are received in peripheral tissues to modulate mitochondrial networks and RNA splicing to promote longevity.