Targeting RNA homeostasis to promote healthy aging

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。 维持健康的蛋白质组对于细胞存活和寿命至关重要，因此，减少蛋白质 内稳态是细胞过程随年龄降低的保真度的基础。迄今为止，干预措施的目的是 保持年轻的蛋白质组集中在DNA> RNA> 蛋白质，靶向调节衰老的转录因子和维持衰老的稳态机制， 正确折叠的蛋白质然而，mRNA加工是DNA和蛋白质之间的关键中间步骤， 然而，RNA稳态和前mRNA剪接效率的维持在很大程度上被忽视， 导致与年龄相关的功能障碍和有机体衰老。我们的初步数据表明RNA 剪接保真度是预期寿命的一个预测因子，而长寿的C.在DR上的elegans保持年轻 剪接模式相比，正常生活的对照动物在相同的实际年龄。展示 因果关系，我们已经确定了DR寿命特别需要的剪接机制的组成部分。我们 因此，中心假设是增强的RNA稳态是DR寿命所必需的， 促进剪接保真度的干预为年龄发作性疾病提供了新的治疗途径。 本申请的目的是确定饮食限制增强剪接的机制 保真度，以增加寿命，以靶向RNA稳态，以促进健康老龄化。我们共同 我希望这项工作是第一次证明RNA稳态下降是生物体 衰老

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. Maintaining a healthy proteome is essential for cellular survival and lifespan, and accordingly, reduced protein homeostasis underlies reduced fidelity of cellular processes with age. To date, interventions aimed towards maintaining a youthful proteome have focused on the two distal ends of the central dogma of DNA > RNA > Protein, targeting both transcriptional factors that regulate aging and homeostatic mechanisms that maintain correctly folded proteins. However, mRNA processing is a key intermediate step between DNA and proteins, yet RNA homeostasis and maintenance of pre-mRNA splicing efficiency have been largely ignored as a contributor to age-related dysfunction and organismal senescence. Our preliminary data demonstrate RNA splicing fidelity is a predictor of life expectancy, and that long-lived C. elegans on DR maintain a youthful splicing pattern compared to normal-lived control animals at the same chronological age. Demonstrating causality, we have identified components of the splicing machinery specifically required for DR longevity. Our central hypothesis is therefore that enhanced RNA homeostasis is required for DR longevity and interventions that promote splicing fidelity present novel therapeutic avenues for age-onset diseases. The objective of this application is to define the mechanism by which dietary restriction enhances splicing fidelity to increase longevity, in order to target RNA homeostasis to promote healthy aging. Collectively, we expect this work to be the first demonstration that RNA homeostasis decline is causal to organismal aging.