Dietary (poly)phenols as modulators of natural killer cell function and immunosenescence: From molecular pathways to clinical evidence

Background: Aging is characterized by immunosenescence, involving the decline of Natural Killer (NK) cell function and persistent low-grade inflammation, increasing susceptibility to age-related diseases. Dietary poly-phenols have emerged as potential agents to mitigate this decline and enhance immune responses. Objective: This systematic review aims to synthesize current evidence on the capacity of dietary polyphenols to modulate Natural Killer (NK) cell plasticity and counteract immunosenescence, offering insights into their potential as therapeutic interventions for healthy aging. Methods: Adhering to PRISMA guidelines, studies investigating NK cells in human, animal, or in vitro aging models, with interventions involving polyphenols or plant extracts, and reporting outcomes such as NK cytotoxicity, cytokine production, senescence markers, or inflammation, were included. Non-English, non-primary research, or studies lacking data on polyphenol-NK interactions were excluded. A comprehensive search was conducted across PubMed, Embase, Web of Science, Scopus, and Cochrane Library from 2010 to June 2025. Risk of bias was assessed using SYRCLE's tool for preclinical studies, Cochrane RoB 2 for clinical trials, and standardized protocols for in vitro studies. Results: 19 studies were included for qualitative and quantitative synthesis. Findings consistently demonstrate that various polyphenols (e.g., resveratrol, verbenalin, catechins, quercetin, polyphenol-rich blueberry extracts) enhance NK cell activation and cytotoxicity, modulate T cell subsets, and improve innate immune functions like phagocytosis and chemotaxis across in vitro, animal, and human models. While in vitro studies generally exhibited a low risk of bias, most in vivo studies were classified with "some concerns" due to reporting limitations in their methodology. Conclusion: Polyphenols exhibit significant dose-and context-dependent immunomodulatory roles, particularly in enhancing NK cell function and mitigating immunosenescence. While preclinical data are promising, further clinical trials addressing bioavailability challenges and interindividual variability are crucial to translating these findings into effective and personalized dietary and therapeutic strategies for promoting immune health in aging populations.