Interactions between aging, dietary restriction, and the gut microbiome

项目总结/摘要 最普遍的疾病-包括心血管疾病，癌症和神经退行性疾病-是 与高龄相关的疾病因此，延缓或逆转衰老机制也可能延缓衰老。 这些常见的毁灭性疾病的发病。延缓衰老最有希望的干预措施之一是 饮食限制（DR），包括禁食和热量限制。在许多不同的动物中，DR可以延长寿命 和healthspan，但仍不完全了解DR如何做到这一点。一个有趣的假设是， 肠道微生物组发挥了作用。例如，将微生物组从DR上的生物体转移到微生物组- 耗尽的接受者改善接受者的健康。为了揭示衰老、DR和 肠道微生物组，在一组遗传异质性小鼠中启动了一项大型纵向实验。 遗传异质性小鼠被用来模拟人类的遗传异质性， 增加研究的人类相关性。在这个实验中，960只6个月大的小鼠被随机分组， 五个饮食组之一：对照组（随意饮食），两个热量限制组（减少20%或40%的热量）， 两个月后，他们将在两个星期内（一天或两天）。粪便样本和广泛的衰老相关表型 每六个月收集一次直到死亡。使用宏基因组测序分析肠道微生物组 粪便样本这一庞大而丰富的数据集将用于1）全面编目老化和DR如何影响 微生物组，以及2）确定DR的哪些益处由微生物组介导。假设来自 该数据集的计算分析将在小型验证实验中进行测试。这项研究的见解将 有助于开发更有针对性和更轻松的新型延长寿命疗法 终身博士。

Project Summary/Abstract The most prevalent diseases—including cardiovascular disease, cancer, and neurodegeneration—are associated with advanced age. Delaying or reversing the mechanisms of aging may therefore also delay the onset of these common and devastating diseases. One of the most promising interventions for delaying aging is dietary restriction (DR), including fasting and caloric restriction. In many different animals, DR extends lifespan and healthspan, but it remains incompletely understood how DR does this. One intriguing hypothesis is that the gut microbiome plays a role. For example, transferring the microbiome from an organism on DR to a microbiome- depleted recipient improves health in the recipient. In order to unravel the interactions between aging, DR, and the gut microbiome, a large, longitudinal experiment was initiated in a cohort of genetically heterogeneous mice. Genetically heterogeneous mice were used to mimic the genetic heterogeneity of humans and therefore to increase the human relevance of the study. In this experiment, 960 mice were randomized at 6 months of age to one of five dietary groups: control (ad libitum diet), two caloric restriction groups (20% or 40% fewer calories), and two fasting groups (one-day fast or two-day fast). Stool samples and extensive aging-associated phenotypes were collected every six months until death. The gut microbiome was profiled using metagenomic sequencing of stool samples. This large and rich dataset will be used to 1) comprehensively catalog how aging and DR affect the microbiome, and 2) to determine which benefits of DR are mediated by the microbiome. Hypotheses from computational analysis of this dataset will be tested in a small validation experiment. Insights from this study will contribute to the development of novel lifespan-extending therapies that are more targeted and less onerous than lifelong DR.