Interactions between aging, dietary restriction, and the gut microbiome

衰老、饮食限制和肠道微生物组之间的相互作用

• 批准号: 10603688
• 负责人: Lev Litichevskiy
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603688
• 关键词: Adherence; Affect; Age; Age Months; Aging; Animals; Body Composition; Caloric Restriction; Calories; Cardiovascular Diseases; Catalogs; Cessation of life; Computational Technique; Computer Analysis; Data Set; Development; Diet; Disease; Eating; Elderly; Environment; Etiology; Fasting; Flow Cytometry; Genetic Heterogeneity; Goals; Health; Health Benefit; Human; Inbreeding; Intervention; Laboratories; Life; Longevity; Malignant Neoplasms; Measurement; Measures; Mediating; Mediation; Meta-Analysis; Metabolic; Methylation; Modeling; Monitor; Mus; Nature; Nerve Degeneration; Organism; Phenotype; Predisposition; Randomized; Running; Taxonomy; Temperature; Testing; Time; Training; Validation; Weight; cohort; dietary; dietary restriction; experimental study; frailty; gut microbiome; healthspan; immune function; improved; insight; machine learning classifier; metagenomic sequencing; microbiome; microbiome research; microbiome signature; model organism; novel; novel therapeutics; peripheral blood; stool sample; theories

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.

项目概要/摘要 最常见的疾病——包括心血管疾病、癌症和神经退行性疾病——是 因此，延缓或逆转衰老机制也可能延缓衰老。 这些常见且具有破坏性的疾病的发生是延缓衰老最有希望的干预措施之一。 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。 和健康寿命，但 DR 是如何做到这一点的仍然不完全清楚。 例如，将微生物组从 DR 上的生物体转移到微生物组中。 耗尽的接受者可以改善接受者的健康状况，以揭示衰老、DR 和疾病之间的相互作用。 针对肠道微生物组，一项大型纵向实验在一群遗传异质的小鼠中启动。 遗传异质小鼠被用来模仿人类的遗传异质性，因此 增加研究的人类相关性 在该实验中，960 只小鼠在 6 个月大时被随机分组​​。 五个饮食组之一：对照组（随意饮食），两个热量限制组（热量减少 20% 或 40%）， 和两个禁食组（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，直到死亡为止，使用宏基因组测序对肠道微生物组进行分析。 这个庞大而丰富的数据集将用于 1) 全面记录衰老和 DR 的影响。 微生物组，2) 确定 DR 的哪些益处是由微生物组介导的。 该数据集的计算分析将在一个小型验证实验中进行测试。 有助于开发更有针对性、更轻松的新型延长寿命疗法 比终身博士。