Interactions between aging, dietary restriction, and the gut microbiome

项目总结/文摘

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.