Relationship of dietary natural folate and synthetic folic acid co-exposure patterns with biological aging: findings from NHANES 2003-2018

Background: The mandatory folic acid fortification program in the United States has inevitably exposed most Americans to both natural folate and synthetic folic acid. We aim to examine the association of dietary folate co-exposure patterns with biological aging indicators. Methods: A total of 18 889 participants were enrolled from 2003 to 2018. Dietary intake of folate from diverse sources was evaluated by 24-hour dietary recall. Biological aging indicators were developed based on age-related clinical indicators, including the phenotypic age (PA), Klemera-Doubal method (KDM), homeostatic dysregulation (HD), and allostatic load (AL). The unsupervised K-means clustering method, logistic regression model, and restricted cubic spline (RCS) regression model were used to explore the relationship of natural folate and synthetic folic acid co-exposure with biological aging indicators. Results: The results indicated that higher intake of total folate, dietary folate, and food natural folate was associated with lower PA [OR = 0.75 (0.64, 0.88); OR = 0.79 (0.70, 0.90); OR = 0.65 (0.57, 0.75)], KDM [OR = 0.63 (0.53, 0.75); OR = 0.80 (0.65, 0.98); OR = 0.62 (0.49, 0.77)], HD [OR = 0.69 (0.56, 0.84); OR = 0.78 (0.67, 0.92); OR = 0.78 (0.68, 0.90)], and AL [OR = 0.69 (0.58, 0.82); OR = 0.73 (0.63, 0.85); OR = 0.74 (0.62, 0.90)], consistently. Four co-exposure patterns were generated based on the intake of folate from diverse sources, as follows: "low folate exposure group" to cluster 1, "dietary folate exposure group" to cluster 2, "mixed source high folate exposure group" to cluster 3, and "mixed source excessive folate exposure group" to cluster 4. Compared with cluster 1, participants in cluster 2 are associated with lower biological age indicators (OR_PA = 0.82 [0.72, 0.93]; OR_KDM = 0.58 [0.47, 0.70]; OR_HD = 0.85 [0.75, 0.97]; OR_AL = 0.87 [0.77, 0.98]), while participants in cluster 3 and cluster 4 are not. Conclusion: For individuals subjected to folic acid fortification programs, a higher intake of dietary folate, especially natural folate, coupled with a lower consumption of folic acid supplements, was found to be associated with lower biological age indicators.