Year: 2023
Type: dissertation
Abstract: Advancing age leads to declines in physiological function and greatly increases risk for the development of numerous diseases, including cardiovascular (CV), neurodegenerative, and metabolic diseases. A key functional decline with aging that contributes to the development of disease is impairments in arterial function, primarily vascular endothelial dysfunction and increases in large elastic artery stiffness. As such, understanding the mechanisms by which arterial function becomes impaired with age and identifying therapeutic targets is of high biomedical relevance. One major mechanism that can contribute to arterial dysfunction with age is the gut microbiome––the collection of trillions of microorganisms that reside within the gastrointestinal tract. Gut microbiota are metabolically active and produce compounds that can enter the host circulation and exert modulatory effects on the vasculature. Despite the largely symbiotic relation between the host and gut microbiome throughout development and adulthood, there are physiological changes that occur with aging that contribute to shifts in the gut microbiome and consequently alter circulating levels of various gut microbiome-derived metabolites. For example, the metabolite trimethylamine N-oxide (TMAO), which contributes to the development of arterial dysfunction and is linked to CVD, increases in circulation with aging. Conversely, production of gut microbiome-derived short-chain fatty acids (SCFA), which have CV health-promoting effects, appears to decrease with age. The purpose of this dissertation research was to identify promising interventions that favorably influence circulating levels of these gut microbiome-derived metabolites and enhance arterial function with aging. First, I found that supplementation with 3,3-dimethyl-1-butanol (DMB), which suppresses gut microbiota-dependent production of TMAO, prevented aspects of age-related arterial dysfunction in mice when initiated in midlife. Second, I found that gut microbial SCFA-producing capacity is decreased with aging in mice, and that supplementation with the SCFA acetate restores artery function in old mice. Together, these studies demonstrate that interventions positively modulating levels of gut microbiome-derived metabolites have efficacy for preserving artery function with aging. Importantly, these interventions have potential for translation to humans for reducing risk of age-related diseases including CV diseases.
Author: Longtine, Abigail Grace
Institutions: University of Colorado Boulder, University of Colorado System
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7029214003