Electronic Theses and Dissertations Archive

Date

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Health Studies

Committee Chair

Brandt Pence

Committee Member

Liza Makowski

Committee Member

Marie van der Merwe

Committee Member

Yufeng Zhang

Abstract

Aging drives systemic functional decline and represents the primary risk factor for comorbidities and mortality. Immune dysregulation is central to chronic age-related inflammation, with macrophages acting as key mediators of unresolved tissue damage. This functional compromise coincides with metabolic maladaptations including elevated mitochondrial stress and impaired mitophagy, which exacerbate oxidative stress and inflammatory overstimulation. However, the exact mechanistic links driving these phenotypes remain incompletely understood. Urolithin A (UA) has emerged as a promising strategy to enhance mitochondrial health via mitophagy stimulation, yet its immunoregulatory effects in the context of aging remain unexplored. Objectives: This study aimed to characterize mitochondrial dysfunction in aged macrophages, delineate the underlying mechanisms, and identify the resulting immune signatures. Additionally, we assessed whether mitophagy stimulation via UA treatment could restore mitochondrial health and immune function. Methods: Bone marrow-derived macrophages from young (3 months) and old (20-22 months) C57BL/6 mice were stimulated in vitro with LPS. To determine the effects of aging on mitochondrial function and quality control, we evaluated complex I and II-linked respiration, as well as autophagy and mitophagy activation. Subsequently, the impact of UA pre-treatment on immunometabolic activation was assessed via mitochondrial stress tests, inflammatory gene expression, phagocytosis, and efferocytosis assays. Results: Aging promoted a higher coupling efficiency in mitochondrial complex I and II respiration, although overall mitochondrial respiration remained unaffected. Furthermore, stimulated aged macrophages exhibited reduced autophagic flux alongside a slight increase in mitophagy. UA treatment effectively enhanced basal and ATP-linked respiration in LPS-stimulated macrophages. In aged macrophages, this was paired with a partial restoration of Tnf expression and the suppression of Il10. However, UA was unable to recover the age-related decline in phagocytosis. Conclusion: This work provides a comprehensive view of the interconnected roles of mitochondrial dynamics and immune responses in aged macrophages. While specific metabolic and autophagic alterations were confirmed, a disruption of overall mitochondrial homeostasis was not observed. Furthermore, although UA effectively improved mitochondrial metabolism, its capacity to rescue broad immune responses was limited.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest/Clarivate.

Notes

Open Access.

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