Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging (“inflammaging”). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

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.