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.

LAST year's double special sections of the Journal on “Anti-Aging Medicine” featured several contributions from the distinguished experimentalist Leonard Hayflick. Among these was “‘Anti-Aging’ is an Oxymoron,”(1) which ends with a question that clearly lays out the importance of the subject of these issues: since there is an “almost universal belief by geriatricians that the greatest risk factor for all of the leading causes of death is old age[,] why then are we not devoting significant resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental question: ‘Why are old cells more vulnerable to pathology than are young cells?’”