High folic acid intake reduces natural killer cell cytotoxicity in aged mice

Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in postmenopausal women ≥ 50 years. NK cells are cytotoxic lymphocytes that are part of the innate immune system critical for surveillance and defense against virus-infected and cancer cells. We determined if a high folic acid diet can result in reduced NK cell cytotoxicity in an aged mouse model. Female C57BL/6 mice (16-month-old) were fed an AIN-93 M diet with the recommended daily allowance (1 × RDA, control) or 20 × RDA (high) folic acid for 3 months. NK cytotoxicity was lower in splenocytes from mice fed a high folic acid diet when compared to mice on control diet (P <.04). The lower NK cell cytotoxicity in high folic acid fed mice could be due to their lower mature cytotoxic/naïve NK cell ratio (P =.03) when compared to the control mice. Splenocytes from mice on high folic acid diet produced less interleukin (IL)-10 when stimulated with lipopolysaccharide (P < .05). The difference in NK cell cytotoxicity between dietary groups was abolished when the splenocytes were supplemented with exogenous IL-10 prior to assessment of the NK cytotoxicity, suggesting that the reduced NK cell cytotoxicity of the high folic acid group was at least partially due to reduced IL-10 production. This study demonstrates a causal relationship between high folic acid intake and reduced NK cell cytotoxicity and provides some insights into the potential mechanisms behind this relationship.