Interactions between aging, dietary restriction, and the gut microbiome

项目摘要/摘要 最常见的疾病--包括心血管疾病、癌症和神经变性--是 与高龄相关的。因此，延缓或逆转衰老机制也可能延缓 这些常见和破坏性疾病的发病。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延长了寿命 和健康寿命，但目前还不完全清楚DR是如何做到这一点的。一个耐人寻味的假设是， 肠道微生物群起着一定的作用。例如，将微生物组从DR上的生物体转移到微生物组- 精疲力竭的接受者改善了接受者的健康。为了揭示衰老、糖尿病和糖尿病之间的相互作用 肠道微生物组，一项大型的纵向实验是在一群遗传异质性的小鼠身上启动的。 遗传异质性的小鼠被用来模拟人类的遗传异质性，因此 增加研究的人性化相关性。在这项实验中，960只小鼠在6个月大的时候被随机分配 到五个饮食组之一：对照组(随意饮食)，两个卡路里限制组(减少20%或40%卡路里)， 两组禁食(禁食一天或禁食两天)。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。利用元基因组测序对肠道微生物组进行分析 大便样本。这一庞大而丰富的数据集将用于1)全面编目老龄化和灾难恢复的影响 微生物组，以及2)确定DR的哪些益处是由微生物组介导的。假设来自 对该数据集的计算分析将在一个小型验证实验中进行测试。从这项研究中获得的见解将 有助于开发更有针对性、负担更少的新的延长生命的疗法 而不是终身博士。

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.