Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

Robert S. Mazzeo

Third Advisor

Nichole Reisdorph

Fourth Advisor

Matthew B. McQueen

Fifth Advisor

Marissa A. Ehringer

Abstract

Advancing age is associated with declines across numerous physiological systems, leading to an increased risk of chronic disease and disability. Whereas aging itself is inevitable, the rate at which physiological impairments occur is highly variable among individuals. Differences in the trajectory of physiological decline are due to complex biological processes; however, the molecular mechanisms underlying physiological impairments are not well understood. Metabolomics provides the unique opportunity to investigate systemic molecular changes in vivo by capturing perturbations in metabolic signaling linked to changes in physiological function. Therefore, the purpose of this dissertation was to determine the relation between metabolomic signatures and age-associated physiological declines in humans.

Global metabolomics profiling of plasma from young and older adults demonstrated changes in metabolomic signatures with advancing age. Pathway analysis of altered metabolites identified amino acid and lipid metabolism as primary pathways modified with age, and targeted metabolomic approaches confirmed these differences. Furthermore, changes in small molecule profiles were related to numerous clinically relevant indicators of human healthspan.

Additionally, in a systems biology approach to further investigate the molecular underpinnings of age-associated physiological declines, metabolomics analyses were applied to a model of biological aging. In a longitudinal study of older adults, biological age was quantified by integrating numerous clinical and physiological measures of human health. Importantly, biological age was significantly related to plasma metabolomic profiles, and these small molecule signatures were also associated with, and predictive of, rates of biological aging.

Collectively, these studies indicate that changes to the plasma metabolome with advancing age are related to physiological dysfunction in older adults. Moreover, these findings not only present valuable insight into pathways that may modulate healthy aging, our results also provide evidence for easily accessible blood-based markers of age-associated physiological declines in humans.

Available for download on Tuesday, August 28, 2018

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