Natural killer cells: gatekeepers of healthy aging in longevity medicine.

Abstract

Natural killer (NK) cells are innate lymphocytes that provide rapid immune surveillance through the recognition and elimination of virally infected, malignant, and stressed cells. Beyond their established roles in host defense, accumulating evidence indicates that NK cells undergo profound age-associated remodeling affecting subset distribution, receptor balance, metabolic programming, and effector function. These changes, collectively referred to as NK immunosenescence, contribute to impaired clearance of senescent cells, dysregulated inflammation, and increased susceptibility to cancer, infection, and metabolic disease. In this review, we integrate current knowledge of NK cell aging into the emerging framework of longevity medicine. Rather than introducing NK cells as a newly identified determinant of aging, we synthesize evidence positioning them as key immune effectors whose functional state reflects and influences biological aging processes. We highlight how NK cells participate in senescence surveillance, tissue homeostasis, and immunometabolic regulation across organs, and how their dysfunction intersects with multiple hallmarks of aging. We further discuss the potential utility of NK-related phenotypic and functional metrics as complementary biomarkers of immune aging, while acknowledging current limitations in specificity and prognostic validation. Finally, we examine therapeutic strategies aimed at preserving or restoring NK competence, ranging from lifestyle and nutritional interventions to cytokine-based therapies, immune checkpoint modulation, and emerging cellular platforms. While many advanced NK-targeted approaches remain investigational-particularly outside oncology settings-we outline a translational roadmap linking NK biology to actionable interventions and measurable outcomes relevant to healthspan. By situating NK cells within a systems-level view of immune aging, this review frames them as a tractable component of precision longevity medicine rather than a singular regulator of aging.