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

Authors: SAWAENGSRI, HATHAIRAT - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, JUNPENG - Translational Medical Center Of Huaihe Clinical College, Henan University; REGINALDO, CHRISTINA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STELUTI, JOSIANE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MEYDANI, SIMIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PAUL POTTENPLACKEL, LIGI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2015
Publication Date: 4/1/2016
Citation: Sawaengsri, H., Wang, J., Reginaldo, C., Steluti, J., Wu, D., Meydani, S.N., Selhub, J., Paul Pottenplackel, L. 2016. High folic acid intake reduces natural killer cell cytotoxicity in aged mice. Journal of Nutritional Biochemistry. 30:102-107.

Interpretive Summary: Consumption of folic acid, the synthetic form of the B vitamin folate, beyond the ability of the body to convert it to biological folate, is associated with reduced natural killer (NK) cell cytotoxicity in post-menopausal women. NK cells are specialized immune cells that are critical to surveillance and defense against virus-infected and cancer cells. To determine if a high folic acid diet can result in reduced NK cell cytotoxicity, aged mice were fed a diet with the recommended dietary allowance (1x RDA, control) or 20x RDA (high) folic acid for 3 months. Mice fed a high folic acid diet had lower NK cell cytotoxicity when compared to mice fed control diet. Mice fed high folic acid had a high proportion of naive and less effective NK cells compared to mature, active NK cells, suggesting that their development process had been impaired.

Technical Abstract: 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 post-menopausal 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-93M diet with the recommended daily allowance (1x RDA, control) or 20x RDA (high) folic acid for 3 months. Mice fed a high folic acid diet had reduced NK cell cytotoxicity in spleen when compared to mice on control diet (P<0.04). The lower NK cell cytotoxicity in high folic acid fed mice could be due to their lower mature cytotoxic/naive NK cell ratio (P=0.03) when compared to the control mice. Splenocytes from mice on high folic acid diet produced less interleukin (IL)-10 when stimulated with lipopolysaccharide (P<0.05). 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.