The Effects of Aging on Circadian Rhythms and the Gut Microbiome
Degree type
Graduate group
Discipline
Public Health
Subject
Dietary restriction
Diversity Outbred mice
Microbiome
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Abstract
Advanced age is the greatest risk factor for the most devastating diseases of our time, including cancer, neurodegeneration, and cardiovascular disease. A better understanding of aging may help us to understand and treat these diseases. Here, I examine in mice how aging affects two aspects of health: circadian rhythms and the gut microbiome. First, I show that aging impairs the diurnal rhythmicity of immune function and gene expression in macrophages. Chromatin accessibility, unlike gene expression, shows no diurnal rhythmicity, suggesting that changes in chromatin accessibility do not drive rhythmic cellular function. Second, I examine a large cohort of genetically diverse mice to assess how aging influences the gut microbiome. This cohort consists of 960 mice assigned to various lifespan-extending dietary interventions. The health of these mice was assessed longitudinally with numerous readouts, and stool samples were collected for characterization of the gut microbiome. I performed metagenomic sequencing of 2997 stool samples to generate the largest-to-date mouse gut microbiome dataset. I find that the microbiome changes with age but that these changes appear to result from stochastic community development, rather than the influence of an aging host. Lastly, I leverage this dataset to describe how dietary restriction and host genetics influence the gut microbiome and, in turn, how the microbiome influences health. I find that the microbiome is associated with several host phenotypes, including body weight and composition, but not with lifespan. In summary, my work advances our understanding of how aging influences two key aspects of health (circadian rhythms and the gut microbiome); cautions against attempting to extend lifespan via gut microbiome interventions; and produced a valuable dataset for the microbiome community.
Advisor
Li, Mingyao