Identification and Characterization of Novel Senescent Cell Biomarker and Age-Dependent Functional Decline Innate Immune Cells in Mice

Author

Ashley Brauning, Dominican University of CaliforniaFollow

ORCID

0000-0002-8318-9165

Graduation Year

2023

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Amit Sharma, PhD

Second Reader

Abdelhadi Rebbaa, PhD

Abstract

Aging is the most significant risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s, and other neurodegenerative diseases of aging, primarily due to the disruption to the homeostasis of our immune system. These chronic inflammatory signals influencing the aging pathology predominantly originate from senescent cells, making them a promising target for therapeutic investigation. However, treatments have remained limited due to the heterogeneity among senescent cells, caused by the vast array of induction events. This project aims 1) investigate differences between senescent and non senescent cells and 2) to gain a better understanding of changes to the innate immune systems ability to clear senescent cells with age.

Utilizing multiple rounds of Peptide Phage Display, an alternative screening method to traditional proteomics approaches that were previously attempted unsuccessfully, we have identified 28 potential peptides that may interact selectively with the surface of senescent cells and through validation have identified five peptides that can specifically interact with the surface of senescent cells, potentially functioning as a novel biomarker for quantifying senescence in vitro and in vivo.

Concurrently, we investigated the age-related impairment to Natural Killer (NK) cells, innate immune cells which function as the primary cells responsible for the immunosurveillance of senescent cells. We utilized a mouse model to characterize the age-related changes to two common NK cell activation markers in mice (NK1.1 and CD49b). We then demonstrate the decreased efficacy of aged NK cells to clear senescent cells via co-culture with senescent fibroblast cells.