Using massive-scale mRNA sequencing to unravel the mechanisms of ageing and its modulation by diet

利用大规模 mRNA 测序揭示衰老机制及其饮食调节

基本信息

批准号：
BB/H008497/1
负责人：
Joao Magalhaes
金额：
$ 41.79万
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2010
资助国家：
英国
起止时间：
2010 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH008497%2F1
关键词：
Using massive scale mRNA sequencing

项目摘要

Elucidating the causal mechanisms of ageing is one of the most pertinent scientific questions of our time. Brain ageing in particular is a major health concern of ageing adults. It is a cause of cognitive decline and a major risk factor for neurodegenerative diseases like Alzheimer's and Parkinson's disease. A major tool available to researchers studying the mechanisms of ageing is caloric restriction (CR) which consists of restricting the normal (Ad lib) food intake of organisms. In different model organisms, including mammals, CR results in a robust extension of lifespan and preservation of health. In rodents, CR has been shown to delay brain ageing. Changes in gene expression levels are associated with many biological processes, cellular responses and disease states. Although several gene expression studies of ageing and CR have been conducted using microarrays, elucidating the transcriptional features of ageing remains a critical challenge. Microarrays have important limitations, for example in terms of low sensitivity to low abundance transcripts. In order to unravel transcriptional networks of ageing and of dietary interventions that modulate ageing, it is necessary to obtain a global view of gene expression changes under ageing and CR. This project will take advantage of next-generation sequencing technology to characterize the ageing gene expression changes with exceptional resolution and provide new mechanistic insights about ageing and its modulation by diet. Genes differentially expressed with age in the rat brain and those whose differential expression with age is attenuated in longer-lived animals will be identified. This will allow molecular biomarkers of brain ageing to be determined with outstanding precision. Alpha-lipoic acid (LA) was recently shown to induce a memory effect in rats switched from CR to Ad lib feeding: animals switching from CR to Ad lib feeding maintained the extended longevity characteristic of CR while conversely animals switching from Ad lib to CR did not exhibit extended longevity. Because LA preserves the longevity benefits of CR animals switched to Ad lib, transcripts identified in these different dietary conditions will be triangulated to identify those transcripts specifically associated with the longevity effects of CR with the memory effects of LA. This will provide insights into the genetic and molecular mechanisms of CR and LA. In conclusion, by employing samples from animals with varying longevity, these studies will provide important mechanistic insights about ageing and its modulation by diet.

阐明衰老的因果机制是我们这个时代最相关的科学问题之一。尤其是大脑衰老是衰老成年人的主要健康问题。这是认知能力下降的原因，也是阿尔茨海默氏病和帕金森氏病等神经退行性疾病的主要危险因素。研究衰老机制的研究人员可获得的主要工具是热量限制（CR），它包括限制有机体的正常（AD LIB）食物摄入。在包括哺乳动物在内的不同模型生物中，CR可实现寿命的强大延长和保留健康。在啮齿动物中，CR已被证明会延迟大脑衰老。基因表达水平的变化与许多生物学过程，细胞反应和疾病状态有关。尽管已经使用微阵列进行了几项对衰老和CR的基因表达研究，但阐明衰老的转录特征仍然是一个关键的挑战。微阵列具有重要的局限性，例如，对低丰度转录本的灵敏度低。为了揭开衰老的转录网络和调节衰老的饮食干预措施的转录网络，有必要在衰老和CR下获得基因表达变化的全球视图。该项目将利用下一代测序技术来表征衰老基因表达的变化，并提供出色的分辨率，并提供有关衰老及其通过饮食调节的新机械见解。将鉴定出在大鼠脑中与年龄差异表达的基因以及在长寿动物中降低年龄差异表达的基因。这将使脑衰老的分子生物标志物以出色的精度确定。最近显示，α-硫酸（LA）可引起从CR转换为AD LIB进食的大鼠的记忆效应：从CR转向AD Lib喂养的动物保持CR的延长寿命特征，而相反的动物从AD LIB转换为CR则没有表现出延长的寿命。由于LA保留了CR动物的寿命益处，因此将在这些不同的饮食条件下确定的转录本将被三角剖分，以识别与LA的记忆效应特别相关的转录本。这将提供有关CR和LA的遗传和分子机制的见解。总之，通过采用来自寿命不同的动物的样品，这些研究将提供有关衰老及其调节的重要机理见解。