Cell Non-autonomous Regulation of Aging via Neuronal TORC1

项目摘要 衰老遗传学领域的进展表明，虽然时间老化是不可避免的， 生物老化是可塑性的，靶向细胞过程以促进体内平衡是一种替代方法 战略，以疾病为基础的方法，以减轻老年人的健康负担。了环境 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 改变他们衰老和疾病的速度，以回应外部线索。最有效的 这方面的例子是饮食限制（DR），减少食物摄入量而不营养不良，这减缓了每个人的衰老。 迄今为止测试的有机体可以预防多种慢性疾病，包括癌症，心血管疾病， 疾病和神经变性。我们的长期目标是阐明DR如何促进健康老龄化 以允许开发治疗年龄相关疾病的新疗法。 多种分子机制已被认为是DR的关键介导物，包括 雷帕霉素复合物1（TORC 1）和AMP激活的蛋白激酶（AMPK），保守的营养传感器， 拮抗调节新陈代谢和衰老。然而，令人惊讶的是，AMPK和TORC 1 相互作用以调节系统老化尚不清楚。我们发现神经元AMPK对于延长寿命至关重要 从C.优雅此外，通过raga-1中的无效突变（上游突变）延长寿命是可能的。 T0 RC 1激活剂）或rsks-1（哺乳动物S6 K的同源物）被神经元特异性recues完全抑制。 神经元RAGA-1通过神经肽信号传导消除raga-1突变体寿命。此前，我们已确定 线粒体动力学和RNA剪接在AMPK和TORC 1寿命调节中的关键作用 分别我们现在表明，这些下游效应器接收由TORC 1介导的神经元信号， 调节衰老。我们的研究结果强调了神经元TORC 1在细胞非自主调控中的新作用， 代谢，RNA稳态和衰老，并建议在中枢神经系统中的TORC 1可能是 以促进健康老龄化为目标。因此，我们的中心假设是，DR的有益效果 可以通过识别由神经元TORC 1调节的细胞非自主信号来概括。 本申请的目的是定义由TORC 1介导的特异性神经元信号，其涉及 健康衰老，以及这些信号如何在外周组织中接收以调节线粒体网络 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.