Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions

Abstract

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.

Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

“…NK cells are mainly involved in antiviral and antitumor response ( 50 – 52 ). ADA2 can bind NK cells, so NK is a target cell to ADA2 ( 23 ).…”

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

“…In the presence of this ligand–receptor interaction, the cell activation is inhibited. In contrast, infected or malignantly transformed cells downregulate MHC-I molecule expression, leading to lower inhibitory signals in NK cells, enabling the NK-mediated elimination of these cells [ 92 ]. Moreover, NK cells can be activated by several cytokines, including IL-12, IL-15, IL-18, and type-I IFNs, during the initial phases of viral infection [ 93 ].…”

“…It is well established that aging is accompanied by changes in NK cell count, phenotype, and function, linked to the risk of several diseases and infections [ 94 ]. However, there is some disagreement regarding the effect of aging on NK cell numbers, probably due to the different surface markers used to quantify them [ 92 ]. Nevertheless, it is generally accepted that aging causes an increase in both the frequency and number of CD3 − CD56 + NK cells [ 95 , 96 , 97 ].…”

“…This reduced lytic capacity also affects the direct elimination of senescent cells. Indeed, the elimination of senescent cells mediated by NK cells declines with advancing age, leading to the accumulation of these cells in the aged tissue and organs, thus hindering tissue homeostasis [ 92 ].…”

“…In particular, zinc supplementation partially restores NK lytic activity, while zinc deficiency correlates with a reduction. Vitamin B9 and B12 supplementation also increase NK cell counts and activity [ 92 ].…”