Graduation Semester and Year

Spring 2024

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Kinesiology

Department

Kinesiology

First Advisor

Daniel W. Trott

Second Advisor

Jody L. Greaney

Third Advisor

Lisa A. Lesniewski

Fourth Advisor

Chueh-Lung Hwang

Abstract

Aging is the major non-modifiable risk factor for cardiovascular disease (CVD), which is the leading cause of death in the United States. Many common CVD are diseases of the arteries. Two major hallmarks of arterial aging are 1) increased large artery stiffness and 2) endothelial dysfunction which is characterized by impaired endothelium dependent vasodilation and blunted nitric oxide (NO) bioavailability. Importantly, these adverse alterations in the arteries occur prior to, and are predictors of the onset of overt CVD. Advancing age is also a non-modifiable risk factor for impaired glucose homeostasis and is directly or indirectly associated with almost every age-related chronic disease, including type 2 diabetes, CVD, frailty, Alzheimer’s disease, dementia, and cancer. Currently, these chronic diseases of aging account for 90% of the annual US health care cost. Thus, understanding the mechanisms responsible for age-related vascular and metabolic impairments are imperative to combat the development of overt cardiovascular and metabolic diseases. Aging is associated with increased levels of basal inflammation which has been implicated to play a role in the development of several age-related diseases, including age-related vascular and metabolic dysfunction. Emerging evidence suggests that T cells, which undergo substantial changes with age, play a mechanistic role in age-related arterial dysfunction and augmented glucose tolerance in old mice. Therefore, understanding how specific subtypes of T cells change with age, and contribute to the diseases of aging will provide novel insights into our fundamental understanding of the pathogenesis of age-related diseases. The overarching hypothesis of this dissertation is to determine how T cells influence vascular and metabolic function with age. Chapters 3 and 4 of this dissertation demonstrate that early life thymectomy results in a T cell phenotype that is similar to aging (i.e., a shift from a naïve towards a memory T cell phenotype) in otherwise young mice. Furthermore, we observe that these changes in T cell phenotype are sufficient to induce both vascular and metabolic dysfunction. These data provide proof of concept that aged T cells alone are sufficient to induce a dysregulated immune system which in turns results in both vascular and metabolic dysfunction in otherwise young animals. Expanding of these findings, Chapter 5 demonstrates that CD8+ rather than CD4+ T cells play a mechanistic role in the development of age-related vascular dysfunction. Bulk RNASeq of CD8+ T cells from old mice reveled that CD8+ T cells which accumulate in the arteries exhibit transcriptional changes in metabolic, functional, and secretory factors compared to CD8+ T cells in the spleen. These results provide novel insights into new potential CD8+ specific targets. Finally, we observe that aging rather than CD8+ or CD4+ T cell specific depletion results in improved glucose tolerance in old mice. Taken together, these data provide evidence that CD8+ T cells are the primary drivers of age-related arterial dysfunction. iv Combined, chapters 3-5 provide proof of concept that T cells contribute to the diseases of aging. Furthermore, this dissertation implicates CD8+ T cells as primary drivers of age-related arterial dysfunction, but do not necessarily influence glucose tolerance in old mice. Future studies should determine the specific mechanisms of CD8+ recruitment and how CD8+ T cells influence arterial and metabolic function in old mice.

Keywords

Aging, T Cells, Arterial Dysfunction, Glucose Intolerance, Thymectomy, Nitric Oxide, Visceral Adipose Tissue, Cytotoxic T Cells

Disciplines

Immunology and Infectious Disease | Laboratory and Basic Science Research | Physiology | Systems and Integrative Physiology

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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Available for download on Thursday, May 07, 2026

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