Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Experimental Pathology

First Advisor

Higgins-Chen, Albert

Abstract

Aging is associated with physiological and molecular decline and a concurrent increase in dysfunction, chronic disease, and mortality. Despite the fact that aging is the greatest risk factor for many chronic diseases, fundamental aging research has historically lagged behind disease-specific research. This deterioration and it’s repercussions has different manifestations in different organs. This dissertation focuses on dynamics of mouse aging with a focus on the liver. The liver's diverse functions are integral to many homeostatic processes, including maintaining metabolic balance, detoxifying harmful substances, supporting immune defense, and regulating blood and endocrine systems. Its impairment can lead to significant health issues. Here, in collaboration with different groups, I explore three aspects of liver aging biology. 1) We analyze the regenerative capacity of the liver, investigating how hepatocyte dynamics contribute to tissue repair after chemical and physical injury. Using multicolor lineage tracing in mouse models, we demonstrate that midlobular hepatocytes predominantly drive homeostatic renewal and recovery, undergoing both hyperplasia and hypertrophy in response to injury. Additionally, we identify the expansion of pericentral hepatocytes, as well as evidence of transdifferentiation and cell fusion. 2) We identify age-invariant genes that maintain consistent expression levels across the lifespan. These genes provide insights into transcriptional resilience and serve as potential reference genes for aging studies. We identify both pan-tissue and tissue-specific reference genes, contributing to the standardization of aging-related molecular research. 3) We make an in depth characterization of liver glucose homeostatic functions and mitochondrial metabolism in age-related insulin resistance. Our group further identifies the transcriptomic and epigenomic changes that occur. Through differential expression and network analysis we uncover molecular changes in genes within and around canonical metabolic pathways. Together, these studiesprovide a comprehensive view of liver aging and regeneration. These findings further the understanding of liver regeneration, provide field-specific reference markers (therefore increasing scientific rigor) and identify molecular changes that could serve as novel markers or targets of liver insulin resistance.

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