DOI
https://doi.org/10.25772/DA8E-2F57
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
Alaattin Kaya
Abstract
Aging is a complex, multifactorial process characterized by a gradual decline in physiological function and increased susceptibility to disease. Although significant progress has been made, the molecular mechanisms underlying aging remain incompletely understood. This doctoral research focuses on two evolutionarily conserved pathways that play critical roles in aging: the tryptophan-kynurenine metabolic pathway and mitochondrial bioenergetics.
In the first part of the study, we investigated the role of the tryptophan-kynurenine pathway in aging using mouse models with whole-body knockouts of indoleamine 2,3-dioxygenase 1 (Ido1), Ido2, and Ido1/Ido2 double knockouts. This pathway represents the primary route for tryptophan catabolism and is essential for regulating immune function, oxidative stress, and NAD⁺ biosynthesis. Tryptophan-derived metabolites modulate neuroinflammation, immune tolerance, and metabolic signaling processes intimately linked to aging and age-related diseases. By utilizing these genetic models, we dissected the individual and combined roles of Ido1 and Ido2 in immune-metabolic regulation and stress adaptation during aging.
In the second part, we employed a novel yeast model to explore how mitochondrial bioenergetics and ATP homeostasis shape cellular aging. Mitochondria are essential for energy production, redox balance, and metabolic signaling. With age, mitochondrial function deteriorates, resulting in diminished oxidative phosphorylation, elevated reactive oxygen species (ROS), and reduced ATP levels—all contributing to cellular decline. Our research examines how cells maintain mitochondrial efficiency during aging and whether enhancing ATP homeostasis can delay age-associated dysfunction.
By integrating findings from both yeast and mouse models, this work identifies conserved molecular mechanisms that regulate immune balance, metabolic health, and cellular energy homeostasis. These insights not only advance our understanding of the biology of aging but also highlight potential therapeutic targets to mitigate age-related diseases.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-8-2025